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Cancer Immunotherapy: Priming the Host Immune Response with Live Attenuated Salmonella enterica.

1. Introduction

Cancer is among the first causes of death in millions of individuals throughout the world [1]. The development of adverse effects and resistance to chemotherapy and radiotherapy, as well as the difficulty inherent to the elimination of metastatic cells, are some of the elements that underscore the need to search for better treatment alternatives with greater selectivity and effectiveness against tumor cells. Recent studies have documented the crucial role of the immune response in the elimination of tumors [2]; this fact has allowed to propose immunotherapy as an encouraging alternative in cancer treatment [3], by potentiating the host immune response activation or by acting in synergy with conventional treatments. In this context, the concept of using bacteria as agents against cancer described over a century ago [4] recently has generated great interest, as a result of the development of live attenuated bacterial vectors safe for human use, such as Salmonella enterica. This bacterium has proven usefulness in antitumoral therapy, by inducing innate and adaptive immune response in preclinical and clinical assays, which has led the tumor elimination without secondary effects [5], making Salmonella enterica a great candidate to cancer immunotherapy.

1.1. Bacteria in Antitumor Immunotherapy. The association of bacteria and antitumor activity was described in 1813, with observations of Vautier on tumor regression in patients with gangrene after Clostridium perfringens infection [6]. Subsequent studies by Coley, documented since 1890, demonstrated that "Coley's toxin," constituted by Streptococcus pyogenes and Serratia marcescens, could immunotherapeutically treat patients with sarcomas, lymphomas, myelomas, and melanomas [4, 7]. Research initiated by Holmgren in 1935 [8], on the antitumor activity of the attenuated strain of Mycobacterium bovis, the Calmette-Guerin Bacillus (BCG), culminated in this approval of this strain in 1976, for intravesical application in patients with bladder superficial transitional cell carcinoma [9], a treatment modality that is currently still in use.

To date, the immunotherapeutic antitumor effect of bacteria has been proven in the genus Bifidobacterium, Clostridium, Listeria, Escherichia, and Salmonella [10, 11]. Among all these bacteria, Salmonella enterica serovar Typhi (Salmonella Typhi) and Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) have been the most studied bacterial vectors in cancer treatment [12]. Some of the characteristics that make these vectors more suitable as antitumor immunotherapy are their property as facultative anaerobe bacteria [10]; their ability to colonize the tumor [13, 14], including metastasis [15]; and their affinity for professional antigen-presenting cells [16, 17], a characteristic associated with the induction or activation mechanisms of the innate immune response [18, 19] and the adaptive antitumor immune response [20, 21]. Furthermore, safe Salmonella enterica vaccine strains, such as Ty21a, are available in the market for human use.

1.2. The Selectivity of Salmonella enterica for Tumor Tissue. Salmonella enterica, a gram-negative bacterium, is highly selective for the tumor environment. However, the mechanisms mediating this characteristic need to be completely elucidated [14]. It has been well documented that tumor microenvironment, characterized by (a) hypoxia, oxygen concentrations [less than or equal to] 10mmHg [10]; (b) the acidity conditioned by lactic acid, resulting from anaerobic metabolism because of decreased oxygen [22]; and (c) necrosis, resulting from tumor cell death due to lack of nutrients and uncontrolled growth [12], can contribute to bacterial proliferation in the tumor tissue. Likewise, some authors have suggested that Salmonella enterica migrates to the tumor tissue attracted by cell components that act as chemotactic agents, such as amino acids and carbohydrates [23, 24]. Recent studies have described the ability of Salmonella Typhimurium to sense the concentrations of ethanolamine, a part of membrane lipids, and hence colonize the gastrointestinal tract [25]. Interestingly, abnormal ethanolamine and other lipid levels of the cell membrane have been detected in different types of neoplasia [26], and they may be acting as chemoattractants of Salmonella enterica to the tumor [27].

On the other hand, there is controversial data on the role played by certain Salmonella enterica proteins involved in their ability to colonize tumor tissue, particularly the two-component system CheA/CheY; some authors mentioned that the presence of this system is indispensable for effective distribution and bacterial recruitment into tumor tissue [23, 24, 28]; its absence leads to decreased tumor colonization due to lower bacterial motility [29]. However, other studies have reported that the lack of CheY protein, as well as other bacterial components involved in motility such as the flagellar components fliA, fliC, and flgE, does not compromise Samonella enterica colonization of tumor tissue [27, 30, 31].

In spite of the discrepancies between the mechanisms used by Salmonella enterica to colonize the tumor, once Salmonella enterica reaches the tumor, its permanence in the tissue is associated to low macrophage and neutrophil activity due to the hypoxia within the tumor [32] and to the suppression of the immune response mediated by cytokines such as TGF-[beta] [19] and the difficult access to the tumor microenvironment of preexisting anti-Salmonella antibodies and complement cascade factors due to the irregular growth of blood vessels in the tumor microenvironment [33]. In great measure, these mechanisms promote the antitumor immunotherapeutic activity of Salmonella enterica on different types of solid and semisolid tumors.

1.3. Intrinsic Oncolytic Activity of Salmonella enterica. Preclinical and clinical studies have demonstrated the intrinsic antitumor capacity of Salmonella enterica (Table 1). This antitumor activity is partly explained by oncolytic mechanisms that are activated because of bacterial incorporation into the tumor microenvironment. Some of these mechanisms (Figure 1) are (1) competition for tumor cell nutrients [12]; (2) release of antitumor bacterial components due to lysis of the bacteria adhered to the tumor cell [34], such as Salmonella enterica nitrate reductase that metabolizes nitrates and nitrites [35], products of the hypoxic tumor environment [36] into nitric oxide (NO) [18], which has the ability to induce tumor cell apoptosis [37]; (3) decreased angiogenesis due to inhibition of the transcription factor HIF-1[alpha] and VEGF [38]; (4) activation of autophagy due to decreased phosphorylation of the proteins AKT and mTOR and increasing proteins as Beclin-1 and LC3 (microtubule-associated protein 1A/1B-light chain 3) [39, 40]; and (5) increased amounts of calreticulin [41], a protein associated to immunogenic cell death that is currently being evaluated as a possible therapeutic alternative in cancer [42].

Although the antitumor mechanisms of Salmonella enterica are not known in detail, several studies have documented this intrinsic activity in different tumor models (Table 1). In 1995, Eisenstein et al. showed that administration of the attenuated strain of Salmonella Typhimurium SL3235 (mutant in the synthesis of aromatic amino acids (aroA)) inhibited the growth and decreased the size of the tumor mass in a plasmacytoma murine model [43]. Subsequent studies reported that attenuated Salmonella enterica strains not only decreased the size of the tumor but also delayed the development of metastases and increased survival in various murine cancer models, including melanoma [44], colon carcinoma [30,45], prostate cancer [46], metastatic T-cell lymphoma [47], and B-cell lymphoma [48]. Similar results were obtained in xenograft mouse models of breast cancer [49] and prostate cancer [50, 51]. In these models, the auxotrophic strains of Salmonella Typhimurium, A1 strain (deficient in leucine and arginine synthesis) and the A1-R strain (deficient in leucine and arginine synthesis, with greater capacity to eliminate tumor cells), maintained their antitumor activity and did not cause toxic effects in the host due to its greater affinity for tumor tissue [49]. The A1-R strain also inhibited bone metastases from breast cancer [52, 53] and the metastases from osteosarcoma [54], pancreatic cancer [55, 56], and dorsal spinal cord gliomas [57].

Additionally, the antitumor efficacy of the A1-R Salmonella enterica strain has been evaluated in vivo in patient-derived orthotopic xenograft (PDOX) murine models [58, 59]. In these models, a fragment of a patient's tumor is surgically grafted into athymic naked mice (nu/nu) and once the mouse develops the tumor, it is treated with the live attenuated bacterium. Metastatic colon cancer PDOX models have also been developed [58], as well as osteosarcoma [60-62], melanoma [63-67], follicular dendritic cell sarcoma [68], and soft tissue sarcoma [69, 70]. These models have shown that the intraperitoneal, intravenous, or intra-arterial administration of Salmonella enterica A1-R colonizes and decreases the size of the tumor. PDOX models have also revealed that Salmonella enterica A1-R can eliminate tumor cells that are resistant to chemotherapeutic agents such as cisplatin [60, 61, 67], doxorubicin [68, 69], and temozolomide [64]. Likewise, Salmonella enterica A1-R eliminated the tumors in PDOX models resistant to kinase inhibitors such as sorafenib [62] and vemurafenib [65]. These studies show the potential clinical usefulness of Salmonella enterica A1-R in antitumor therapy.

Some clinical trials have reported the use of live attenuated Salmonella enterica strains in the treatment of cancer. A phase I clinical study using the VNP20009 strain of Salmonella Typhimurium, with mutations in the msbB genes (affecting the formation of lipid A, decreasing the toxicity associated to the lipopolysaccharide) and purI genes (turning it dependent on an external adenine source), included 24 patients with metastatic melanoma and 1 patient with metastatic renal cell carcinoma; in the study, patients that received an intravenous dose of the VNP20009 strain did not develop adverse reactions to the Salmonella enterica infection, but bacterial colonization was moderate and the antitumor effect was not significant [71]. Further studies have shown that the antitumor activity failure could have resulted from low bacterial colonization of the tumor tissue, since the VNP20009 strain has a polymorphism in the CheY gene [29] and a mutation in the msbB gene [72], associated with low strain motility. Indeed, the presence of previous antibodies against Salmonella enterica could also have been a factor compromising antitumor activity [73].

1.4. Activation of the Antitumor Innate Response by Salmonella enterica. In the tumor microenvironment, immunosurveillance evasion mechanisms prevent the eradication of tumor cells [2] and represent a barrier that Salmonella enterica must overcome when used as an immunotherapeutic agent. The first studies describing the antitumor immunotherapeutic properties of Salmonella enterica were conducted by Kurashige et al., using minicells (vesicles with no genomic DNA) obtained from Salmonella Typhimurium, and evaluated in two different murine models (sarcoma [74] and T-cell lymphoma [75]); they observed that the administration of these minicells restored macrophage activity in the tumor microenvironment, promoting tumor elimination. Recent studies have reported that some of the mechanisms that could use the bacterium to eliminate the tumor cells once it is in the tumor microenvironment involved enhance the expression of soluble mediators such as inducible nitric oxide synthase (iNOS) and interferon [gamma] (IFN-[gamma]) and also inhibit the expression of immunosuppressive factors such as arginase-1, interleukin-4 (IL-4), transforming growth factor-[beta] (TGF-[beta]), and vascular endothelial growth factor (VEGF) [19] (Figure 2(a)). In addition, Salmonella enterica also can decrease the activity of myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment [76] and promotes the recruitment of NK cells [77], neutrophils [18], macrophages [19], and T [21] and B lymphocytes [20] into the tumor microenvironment and spleen [41].

Other studies have documented the ability of Salmonella enterica to suppress tumor growth inducing inflammasome [78], by activation of interleukin-1[beta] (IL-1[beta]) and TNF-[alpha] [79]. Likewise, Salmonella enterica also increases the levels of proinflammatory cytokines while decreasing the levels of antiinflammatory cytokines in the tumor microenvironment [80], and this modulation of cytokines may result from the activation of Toll-like receptors (TLRs) in the tumor tissue.

1.5. Antitumor Response of Salmonella enterica by TLR Activation. Activation of the host innate immune response via TLRs is one of the therapeutic strategies against cancer that has begun to be evaluated [81]. Studies in which TLR4 is activated by Salmonella choleraesuis revealed less tumor growth in a melanoma murine model, and this decrease was associated to the recruitment of innate immune response cells such as neutrophils and macrophages [82]. On the other hand, the activation of TLR5 by the flagellin of Salmonella Typhimurium fused with peptide P10 of the gp43 protein of Paracoccidioides brasiliensis eliminated the development of metastases in the melanoma murine model [83], and the use of a TLR5 agonist displayed antitumor effects in a murine lymphoma model while also promoting the activation of [CD8.sup.+] lymphocytes and NK cells [84]. Although, these studies showed a possible role of TLR5 in cancer treatment, a recent study conducted by J.H. Zheng et al. that evaluate the antitumor effect of TLR4 and TLR5 by Salmonella enterica, using knockout (KO) mice for these receptors, shown differences in the antitumor capacity between both receptors. In this study, mice bearing colon cancer or melanoma implant were treated with a Salmonella Typhimurium that expresses flagellin B (FlaB) of Vibrio vulnificus. The results showed that TLR4 KO mice had exacerbated tumor development, similar to those seen in mice that were not treated with Salmonella Typhimurium; on the other hand, TLR5 KO mice showed a partial decrease in tumor growth. Total tumor reversal was observed, as expected, in wild-type mice that had also been implanted with tumor cells and treated with the same Salmonella Typhimurium expressing FlaB [85]. This data shows that the main effect of this bacterium was mediated by TLR4 activation, while TLR5 plays a less decisive role in tumor suppression. These observations are consistent with results from other studies, in which the administration of Salmonella Typhimurium flagellin in a breast cancer murine model had no significant antitumor effect if the flagellin is administered after tumor implantation, but interestingly, the simultaneous administration of flagellin and tumor cells promoted faster tumor development in the mice [86]. Studies conducted in a multiple myeloma cell line support the controversial data on the role of TLR5, since its activation promoted the proliferation and tumor cell survival [87].

1.6. Tumor Cell Immune Response to Salmonella Infection. The recruitment of immune response cells in the tumor microenvironment, including NK cells (natural killer), neutrophils [18], macrophages [19], T lymphocytes [21], and B lymphocytes [20], has been described as one of the main mechanisms through which Salmonella enterica is able to eliminate tumor cells. Although the mechanisms involved in the initial recruitment of these cells, after intratumoral administration of Salmonella enterica, remain under study [88], this process could begin by recognizing bacterial LPS via TLR4, leading to increased TNF-[alpha] levels [89], which provoke hemorrhage from the blood vessels in the tumor, thus promoting infiltration of the immune response cells, which will initiate the tumor elimination process [90] (Figure 2(b)). On the other hand, B and T lymphocyte responses resulting from the administration of Salmonella enterica also play a significant role in the antitumor effect. In this context, the depletion of B lymphocyte promotes preferential colonization of Salmonella enterica in tumor tissue and also in organs such as the spleen and liver and increases the permanence of bacterium in the blood [20]. However, these colonization differences were not observed after depletion of [CD4.sup.+] and/or [CD8.sup.+] cells, but a decrease in the recruitment of neutrophils and macrophages in tumor tissue was observed [21].

Further, the antitumor effect of Salmonella enterica also includes the dendritic cells (DCs). A study by Shilling et al. [91] showed that in vitro activation of purified murine DCs with cytoplasmic Salmonella Typhimurium fractions and tumor-derived heat shock proteins prevented tumor formation after DCs activated were reinoculated in mice; however, DCs that were only activated with the cytoplasmic fractions of bacterium or with the tumor-derived heat shock proteins did not prevent tumor growth. Additionally, they showed that DCs activated were preferentially localized in the tumor, followed by lymph nodes and in a lower proportion, in the liver, lung, and spleen. Other studies have documented that Salmonella enterica also favors the cross-presentation of tumor antigens by DCs and induces [CD8.sup.+] lymphocyte activation capable of recognizing tumor cells [80]; this could be associated with the generation of a protective effect that prevents tumor relapse [89]. Nevertheless, the last date must be confirmed, since a study conducted in a murine melanoma model revealed a specific response against the tumor mediated by [CD8.sup.+] lymphocytes but did not induce an immunologic memory [92].

Moreover, several studies have documented that Salmonella enterica triggers tumor regression by reverting its immune tolerance, through two possible mechanisms: (1) by decreasing the amount of T-regulatory lymphocytes [CD4.sup.+] [CD25.sup.+] (Treg) in tumor tissue by the effect of LPS and the Braun lipoprotein (Lpp) of Salmonella enterica, because mutations in msbB gene and IppA e IppB genes (Lpp) do not decrease the number of Treg lymphocytes in the tumor [93], and (2) by decreasing the levels of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1) [40], an enzyme of tryptophan metabolism associated to the development of immune tolerance in T lymphocytes [94, 95], preventing the formation of kynurenine and promoting the proliferation of T lymphocytes capable of recognizing and eliminating the tumor.

1.7. Induction of the Antitumor Adaptive Immune Response by Salmonella enterica. The adaptive immune response also plays an important role in the antitumor activity induced by Salmonella enterica, because the response against Salmonella enterica antigens has been considered as a possible mechanism for tumor elimination [96, 97]. Although the mechanism is not completely understood, it has been proposed that once the bacterium reaches the tumor microenvironment, infected tumor cells are capable to process and present Salmonella enterica antigens to cytotoxic T lymphocytes that eliminate infected cells; this process has been observed in solid tumors and their metastases [50, 98], as well as, nonsolid tumors [77]. Other mechanism that could use Salmonella enterica to activate immune response is enhancing the expression of connexin 43 (Cx43) [99], a protein associated to B and T lymphocyte activation [100], and promotes the cross-presentation of tumor cell antigens by dendritic cells [101], through the formation of gap junctions that allow the passage of preprocessed tumor cell peptides into the dendritic cell for adequate presentation by MHC class I [99], thus favoring the [CD8.sup.+] T antitumor lymphocytes (Figure 2(c)). Other studies have described the ability of Salmonella enterica to induce T lymphocyte proliferation [40] and increase the levels of antitumor proinflammatory cytokines [80]. For instance, in a murine B-cell lymphoma model, the administration of Salmonella Typhimurium induced a local and systemic adaptive antitumor immune response, characterized by the recruitment of [CD8.sup.+] and [CD4.sup.+] lymphocytes into the tumor [77]; likewise, it was observed that the lymphocytes obtained from the spleen of these mice secreted proinflammatory cytokines, such as IFN-[gamma] and IL-12, in response to the specific stimulus by tumor cells, and the analysis of the humoral response revealed the presence of specific antibodies against tumor cells, which contribute to tumor eradication (Figure 2(d)).

1.8. Salmonella enterica as Delivery System of Tumor-Associated Antigens or Tumor-Specific Antigens for Cancer Therapy. Although many studies using murine models have shown the oncolytic activity of Salmonella enterica, in a clinical trial, it was observed that bacterium was not sufficient to eliminate the tumor [71]. In order to improve the antitumor potency of this bacterial vector, Salmonella enterica has been used as a delivery system of tumor-associated antigen (TAA) or tumor-specific antigen (TSA) [102] (Table 2), proteins expressed on tumor cells that promote transformation and tumorigenesis. The expression of these antigens on Salmonella enterica has the purpose of inducing or potentiating the specific immune response against the tumor, considering the great tropism of Salmonella enterica for professional antigen-presenting cells [103]. With this purpose, the expression and releasing of TAA/TSA through type 1 (T1SS) and type 3 (T3SS) secretion systems of Salmonella enterica have been documented. For instance, mice immunization with a Salmonella Typhimurium strain that released prostate-specific antigen (PSA) via the HlyA (T1SS) system activated an immune response mediated by [CD8.sup.+] T lymphocytes, which inhibited tumor development [104]. Likewise, immunization of a murine pulmonary adenoma model with Salmonella Typhimurium overexpressing the C-Raf antigen (a molecule with a central role in carcinogenesis) induced antibodies against this protein, generating an antigen-specific T-cell response and inhibiting tumor growth [105]. Moreover, the release of peptide of the Listeria monocytogenes p60 protein, simulating the presence of a tumor antigen via T3SS of Salmonella Typhimurium in a fibrosarcoma murine model, demonstrated that 80% of mice immunized were protected after a fibrosarcoma tumor cell challenge that expressed the p60 peptide; this effect would be associated to the presence of [CD8.sup.+] T lymphocytes specific against this peptide [106, 107]. Similar results have been observed after oral immunization with an attenuated strain of Salmonella enterica that releases the tumor antigen NY-ESO-1 (a protein in germ cells that is overexpressed in cancer of the lung, melanoma, esophagus, ovary, bladder, and prostate) via T3SS [108]. Likewise, orogastric immunization with Salmonella Typhimurium, which translocates the immunogenic epitope of the murine vascular endothelial growth factor receptor 2 (VEGFR-2) via T3SS, induced an antigenspecific immune response by [CD8.sup.+] T lymphocytes, in a murine melanoma model, and decreased metastases up to 60% in the immunized mice [109]. Other study showed that the release of the recombinant protein E7/SipB (E7 protein of the human papillomavirus, type 16/SipB, protein of T3SS) in a cervical cancer murine model inhibited tumor growth to 45% and promoted mouse survival up to 70% [110].

On the other hand, the ability of Salmonella enterica to transfer nucleic acids into a eukaryote cell (bactofection) has also been evaluated in the generation of a tumor antigen-specific immune response. In this context, the bactofection of the L1 HPV16 gene, which encodes the capsid protein of the type 16 human papillomavirus, in cervical cancer murine model with a strain of Salmonella enterica, led to tumor regression and increased the survival of mice [111]. Likewise, in a breast cancer murine model in which Salmonella enterica performed the bactofection of the gene encoding the protein MTDH/AEG1-1, an oncogene associated to angiogenesis that is overexpressed in 40% of breast cancer patients, tumor regression was also observed as well as increased survival of the mice [112].

Salmonella enterica was recently used to transport 41IBBL molecules, a member of the TNF family, and CEACAM 6 molecules, a cellular adhesion molecule, in a rat colon cancer model; the immunization with Salmonella enterica carrying those antigens avoided tumor progression, decreased the numbers of Treg cells, promoted a Th1 response, and increased the numbers of CD45RO+ memory T-cells [113].

1.9. Salmonella enterica as Delivery System of Immunomodulating and Apoptosis-Inducing Proteins for Cancer Therapy. The use of Salmonella enterica as a tumor antigen carrier in [CD4.sup.+] and [CD8.sup.+] T lymphocyte activation is limited to those immunogenic tumors expressing associated or specific tumor antigens [13]. An alternative to this inconvenience is the use of Salmonella enterica as a delivery system of molecules that modulate the immune response of the host, facilitating the elimination of tumor. Salmonella Typhimurium has indeed been used to transport immunomodulating proteins such as LIGHT [114], interleukin-18 [115], and the chemokine CCL21 [33], in breast cancer and colon cancer murine models; in all cases, regression of the primary tumor was observed as well as of its pulmonary metastases, where the antitumor activity was associated to the recruitment of DCs, macrophages, neutrophils, NK cells, and lymphocytes. Other studies conducted with Salmonella Typhimurium expressing human interleukin-2 prevented the formation of pulmonary metastases in an osteosarcoma murine model in which NK cells were possibly responsible for the tumor regression [116, 117]. Also, the use of Salmonella enterica in the bactofection of plasmids encoding interleukin-4 or interleukin-18 induced a systemic increase in IFN-[gamma] and was efficient in delaying tumor growth and prolonging survival in a melanoma murine model [118] (Table 2).

Additionally, aside from the expression of immunemodulating molecules, Salmonella enterica has also been used to express and/or secrete molecules that induce tumor cell death by apoptosis, such as Fas ligand [119], TNF-[alpha] [120], or TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) [121], in murine models of colon cancer, melanoma, or gastric cancer, respectively; in all cases, significant tumor regression was observed as well as increased mouse survival.

1.10. Is Salmonella Typhi the Most Appropriate Immunotherapeutic Agent? Most studies documenting the role of Salmonella enterica as an antitumor immunotherapeutic agent have been conducted with the attenuated Salmonella Typhimurium strain, a species that in case of pathogenicity would only cause a mild infection in humans, since it preferentially infects mice [96]. However, the modest antitumor activity induced by this species in clinical trials [71] raises the possibility of using Salmonella Typhi vaccine strains (whose natural host is the human), such as the Ty21a strain [122] and the CVD915 strain [123], for antitumor immunotherapeutic purposes in humans. There are a few studies evaluating the ability of these Salmonella Typhi vaccine strains to act as immunotherapeutic agents. The CVD915 strain was evaluated in a breast cancer murine model, and it delayed tumor growth in association with [CD8.sup.+] and B220+ lymphocyte activation, but not [CD4.sup.+] cells. Another study revealed that the administration of this same strain decreased the amount of Treg lymphocytes in the tumor area [124]. Additionally, in a T-cell lymphoma murine model treated with the CVD915 strain, a decrease in metastasis toward lymph nodes was observed [47]. These results were consistent with those obtained in a breast cancer murine model, in which the administration of Salmonella Typhi CVD915 prevented metastasis development due to previous activation of B and T lymphocytes and DCs [125]. Also, studies using the Ty21a vaccine strain in a bladder cancer murine model led to tumor regression by [CD8.sup.+] T lymphocyte activation and the expression of chemokines such as CXCL5, CXCL2, CCL8, and CCL5 [126]. These results have established the basis for the use of strains such as Salmonella Typhi Ty21a with antitumor purposes. Recently, a phase I clinical trial was conducted in patients with stage IV pancreatic cancer, which used Salmonella Typhi Ty21a for bactofection of a plasmid with the human VEGFR-2 sequence (overexpressed protein on endothelium of tumor microenvironment); its aim was to induce an antiangiogenic response and memory immune response against endothelial cells to eliminate tumor vascularization [127]. Preliminary results revealed that treatment with Salmonella Typhi Ty21a was well tolerated by patients and led to significant tumor regression [128]. This data significantly reinforces the use of Salmonella Typhi as an antitumor immunotherapeutic agent that can be used in a biosafety manner in the treatment of cancer.

2. Conclusion

Bacteria played a key role in the early stages of antitumor immunotherapy with the use of Coley's toxin [4], a therapeutic modality that was substituted by the advent of radiotherapy and chemotherapy. However, the use of the attenuated strain of Mycobacterium bovis, BCG, in the treatment of patients with superficial transitional cell bladder cancer is an active option to this day [9]. This review has described in detail the use of live attenuated Salmonella enterica as the immunotherapeutic bacterial vector par excellence, in cancer treatment. This bacterium fulfills all the characteristics required by a live attenuated bacterial vector to act as an immunotherapeutic agent [129]: (a) its biology must be fully known, including its facultative anaerobe property [96], which facilitates its selectivity for the tumor microenvironment and its intrinsic oncolytic activity; (b) for decades, it has been described as a bacterial vector with vaccine purposes due to its high affinity for professional antigen-presenting cells, favoring immunotherapeutic activity in the induction of the innate and adaptive antitumor immune responses [16, 17]; (c) there are biologically safe attenuated strains for immunotherapeutic use in humans [71, 127, 128]; and (d) its capacity as a delivery system of immunomodulating molecules [33, 115, 116] and TAA/TSA [53, 105, 109] has been proven to facilitate antitumoral immunotherapeutic activity.

Finally, based on the above mentioned studies, we can conclude that Salmonella enterica may be currently considered a live attenuated bacterial vector with great potential in the field of cancer immunotherapy.

2.1. Future Directions. Over a century and a half after the first reports on bacterial antitumor activity [7, 130], live attenuated Salmonella enterica has been consolidated as an ally in cancer therapy [5, 11, 12, 131]. However, although some clinical trials have been reported (Tables 1 and 2), their number should be increased with different malignant neoplasms using Salmonella enterica as an alternative antitumor therapy, including the possibility of using the bacterium in combination with chemotherapeutic agents [132]. Research efforts also should be focused on developing better and biosafe live attenuated strains, optimizing the production and transport mechanisms of antitumor molecules into the cell or cellular microenvironment, and improving the bacterium's selectivity for the cell or tumor tissue. Regarding the development of live attenuated biosafe strains, aside from using Salmonella Typhimurium strain VNP20009 that has been proven to be well tolerated by patients with metastatic melanoma, metastatic renal carcinoma, head and neck carcinoma, and esophageal adenocarcinoma [71, 133, 134], recent studies have focused on the use of Salmonella Typhi strain Ty21a, a biosafe strain approved for human use as a vaccine [127]. In this context, some options that should be evaluated in antitumor therapy in its clinical phases are the Salmonella Typhi CVD908, CVD908-htrA, and Ty800 strains that have also been proven to be safe in vaccine clinical trials [17, 135]. Several efforts have been described to improve the production and transport of antitumor molecules into the cell or cellular microenvironment, as reflected in recent studies describing a Salmonella enterica with a self-limited lifecycle controlled by a lysis circuit that allows the bacterium to release in an oscillatory manner the cytotoxic antitumor molecule [136]; an interesting strategy that could be evaluated is to use the bacterial secretion systems, such as type V or autotransporter, a mechanism present in Salmonella enterica that could release antitumor heterologous molecules coupled to peptides that destabilize cell membranes in order to reach the target in the tumor cell [11, 137]. Increasing the bacterium's selectivity for the cell or tumor tissue will help decrease the secondary effects inherent to the bacterium's intrinsic toxicity; some improvements have been developed by coupling single-domain antibodies to the surface of Salmonella Typhimurium SL3262 in order to increase the bacterium's specificity for the tumor microenvironment [138]. Another alternative that could increase this selectivity and that should be evaluated is the use of synthetic adhesins fused to the variable domains of the antibody's heavy chain that once expressed in bacteria and have shown to be efficient in colonizing tumors expressing some antigen recognized by the synthetic adhesin [139].

Accordingly, obtaining the best live attenuated and biosafe strains, clinically tested, which induce minimal side effects and that still exert their antitumor effect, will allow to confirm that live attenuated Salmonella enterica is the vector par excellence in cancer immunotherapy.

Conflicts of Interest

The authors declare no conflicts of interest of any nature.


Rosendo Luria-Perez acknowledges support from Consejo Nacional de Ciencia y Tecnologia (CB-2013-01-222446, INFR-2015-01-255341, and PN-2015-01-1537) and Fondos Federales (HIM-2016-114 SSA. 1333). Marco Antonio Hernandez-Luna acknowledges support from SICES (IJS/ CON/102/2017UG).


[1] A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, "Global cancer statistics," CA: A Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69-90, 2011.

[2] G. P. Dunn, L. J. Old, and R. D. Schreiber, "The immunobiology of cancer immunosurveillance and immunoediting," Immunity, vol. 21, no. 2, pp. 137-148, 2004.

[3] J. D. Wolchok and T. A. Chan, "Cancer: antitumour immunity gets a boost," Nature, vol. 515, no. 7528, pp. 496-498, 2014.

[4] W. B. Coley, "Contribution to the knowledge of sarcoma," Annals of Surgery, vol. 14, no. 3, pp. 199-220, 1891.

[5] H. Chavez-Navarro, D. D. Hernandez-Cueto, A. Vilchis-Estrada, D. C. Bermudez-Pulido, G. Antonio-Andres, and R. Luria-Perez, "Salmonella enterica: an ally in the therapy of cancer," Boletm Medico del Hospital Infantil de Mexico, vol. 72, no. 1, pp. 15-25, 2015.

[6] C. Zu and J. Wang, "Tumor-colonizing bacteria: a potential tumor targeting therapy," Critical Reviews in Microbiology, vol. 40, no. 3, pp. 225-235, 2014.

[7] J. M. Pawelek, K. B. Low, and D. Bermudes, "Bacteria as tumour-targeting vectors," The Lancet Oncology, vol. 4, no. 9, pp. 548-556, 2003.

[8] G. Mastrangelo, E. Fadda, and G. Milan, "Cancer increased after a reduction of infections in the first half of this century in Italy: etiologic and preventive implications," European Journal of Epidemiology, vol. 14, no. 8, pp. 749-754, 1998.

[9] A. M. Kamat and D. L. Lamm, "Immunotherapy for bladder cancer," Current Urology Reports, vol. 2, no. 1, pp. 62-69, 2001.

[10] M. Q. Wei, K. A. O. Ellem, P. Dunn, M. J. West, C. X. Bai, and B. Vogelstein, "Facultative or obligate anaerobic bacteria have the potential for multimodality therapy of solid tumours," European Journal of Cancer, vol. 43, no. 3, pp. 490-496, 2007.

[11] M. A. Hernandez-Luna, R. Luria-Perez, and S. Huerta-Yepez, "Therapeutic intervention alternatives in cancer, using attenuated live bacterial vectors: Salmonella enterica as a carrier of heterologous molecules," Revista de Investigacion CUnica, vol. 65, no. 1, pp. 65-73, 2013.

[12] N. S. Forbes, "Engineering the perfect (bacterial) cancer therapy," Nature Reviews Cancer, vol. 10, no. 11, pp. 785-794, 2010.

[13] M. Moreno, M. G. Kramer, L. Yim, and J. A. Chabalgoity, "Salmonella as live Trojan horse for vaccine development and cancer gene therapy," Current Gene Therapy, vol. 10, no. 1, pp. 56-76, 2010.

[14] J. M. Pawelek, K. B. Low, and D. Bermudes, "Tumor-targeted Salmonella as a novel anticancer vector," Cancer Research, vol. 57, no. 20, pp. 4537-4544, 1997.

[15] S. Ganai, R. B. Arenas, J. P. Sauer, B. Bentley, and N. S. Forbes, "In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis," Cancer Gene Therapy, vol. 18, no. 7, pp. 457-466, 2011.

[16] S. Spreng, G. Dietrich, and G. Weidinger, "Rational design of Salmonella-based vaccination strategies," Methods, vol. 38, no. 2, pp. 133-143, 2006.

[17] X. L. Zhang, V. T. Jeza, and Q. Pan, "Salmonella typhi: from a human pathogen to a vaccine vector," Cellular & Molecular Immunology, vol. 5, no. 2, pp. 91-97, 2008.

[18] Y. Barak, F. Schreiber, S. H. Thorne, C. H. Contag, D. Debeer, and A. Matin, "Role of nitric oxide in Salmonella typhimurium-mediated cancer cell killing," BMC Cancer, vol. 10, no. 1, p. 146, 2010.

[19] S. Kaimala, Y. A. Mohamed, N. Nader et al., "Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity," Cancer Immunology, Immunotherapy, vol. 63, no. 6, pp. 587-599, 2014.

[20] C. H. Lee, J. L. Hsieh, C. L. Wu, H. C. Hsu, and A. L. Shiau, "B cells are required for tumor-targeting Salmonella in host," Applied Microbiology and Biotechnology, vol. 92, no. 6, pp. 1251-1260, 2011.

[21] C. H. Lee, J. L. Hsieh, C. L. Wu, P. Y. Hsu, and A. L. Shiau, "T cell augments the antitumor activity of tumor-targeting Salmonella," Applied Microbiology and Biotechnology, vol. 90, no. 4, pp. 1381-1388, 2011.

[22] U. E. Martinez-Outschoorn, M. Peiris-Pages, R. G. Pestell, F. Sotgia, and M. P. Lisanti, "Cancer metabolism: a therapeutic perspective," Nature Reviews Clinical Oncology, vol. 14, no. 1,pp. 11-31, 2017.

[23] R. W. Kasinskas and N. S. Forbes, "Salmonella typhimurium specifically chemotax and proliferate in heterogeneous tumor tissue in vitro," Biotechnology and Bioengineering, vol. 94, no. 4, pp. 710-721, 2006.

[24] R. W. Kasinskas and N. S. Forbes, "Salmonella typhimurium lacking ribose chemoreceptors localize in tumor quiescence and induce apoptosis," Cancer Research, vol. 67, no. 7, pp. 3201-3209, 2007.

[25] C. J. Anderson, D. E. Clark, M. Adli, and M. M. Kendall, "Ethanolamine signaling promotes Salmonella niche recognition and adaptation during infection," PLoS Pathogens, vol. 11, no. 11, article e1005278, 2015.

[26] M. Cheng, Z. M. Bhujwalla, and K. Glunde, "Targeting phospholipid metabolism in cancer," Frontiers in Oncology, vol. 6, p. 266, 2016.

[27] C. A. Silva-Valenzuela, P. T. Desai, R. C. Molina-Quiroz et al., "Solid tumors provide niche-specific conditions that lead to preferential growth of Salmonella," Oncotarget, vol. 7, no. 23, pp. 35169-35180, 2016.

[28] B. J. Toley and N. S. Forbes, "Motility is critical for effective distribution and accumulation of bacteria in tumor tissue," Integrative Biology, vol. 4, no. 2, pp. 165-176, 2012.

[29] K. M. Broadway, E. A. P. Denson, R. V. Jensen, and B. E. Scharf, "Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009," Journal of Biotechnology, vol. 211, pp. 117-120, 2015.

[30] K. Crull, D. Bumann, and S. Weiss, "Influence of infection route and virulence factors on colonization of solid tumors by Salmonella enterica serovar Typhimurium," FEMS Immunology & Medical Microbiology, vol. 62, no. 1, pp. 75-83, 2011.

[31] J. Stritzker, S. Weibel, C. Seubert et al., "Enterobacterial tumor colonization in mice depends on bacterial metabolism and macrophages but is independent of chemotaxis and motility," International Journal of Medical Microbiology, vol. 300, no. 7, pp. 449-456, 2010.

[32] K. Westphal, S. Leschner, J. Jablonska, H. Loessner, and S. Weiss, "Containment of tumor-colonizing bacteria by host neutrophils," Cancer Research, vol. 68, no. 8, pp. 2952-2960, 2008.

[33] M. Loeffler, G. le'Negrate, M. Krajewska, and J. C. Reed, "Salmonella typhimurium engineered to produce CCL21 inhibit tumor growth," Cancer Immunology, Immunotherapy, vol. 58, no. 5, pp. 769-775, 2009.

[34] A. Eisenstark, R. A. Kazmierczak, A. Dino, R. Khreis, D. Newman, and H. Schatten, "Development of Salmonella strains as cancer therapy agents and testing in tumor cell lines," Methods in Molecular Biology, vol. 394, pp. 323-354, 2007.

[35] M. P. Spector, F. Garcia del Portillo, M. J. Pallen et al., "The rpoS-dependent starvation-stress response locus stiA encodes a nitrate reductase (narZYWV) required for carbon-starvation-inducible thermotolerance and acid tolerance in Salmonella typhimurium," Microbiology, vol. 145, no. 11, pp. 3035-3045, 1999.

[36] J. M. Brown and W. R. Wilson, "Exploiting tumour hypoxia in cancer treatment," Nature Reviews Cancer, vol. 4, no. 6, pp. 437-447, 2004.

[37] L. M. McLaughlin and B. Demple, "Nitric oxide-induced apoptosis in lymphoblastoid and fibroblast cells dependent on the phosphorylation and activation of p53," Cancer Research, vol. 65, no. 14, pp. 6097-6104, 2005.

[38] D. G. Tu, W. W. Chang, S. T. Lin, C. Y. Kuo, Y. T. Tsao, and C. H. Lee, "Salmonella inhibits tumor angiogenesis by downregulation of vascular endothelial growth factor," Oncotarget, vol. 7, no. 25, pp. 37513-37523, 2016.

[39] C. H. Lee, S. T. Lin, J. J. Liu, W. W. Chang, J. L. Hsieh, and W. K. Wang, "Salmonella induce autophagy in melanoma by the downregulation of AKT/mTOR pathway," Gene Therapy, vol. 21, no. 3, pp. 309-316, 2014.

[40] Y. D. Kuan and C. H. Lee, "Salmonella overcomes tumor immune tolerance by inhibition of tumor indoleamine 2, 3-dioxygenase 1 expression," Oncotarget, vol. 7, no. 1, pp. 374-385, 2016.

[41] B. Chirullo, S. Ammendola, L. Leonardi et al., "Attenuated mutant strain of Salmonella Typhimurium lacking the ZnuABC transporter contrasts tumor growth promoting anti-cancer immune response," Oncotarget, vol. 6, no. 19, pp. 17648-17660, 2015.

[42] G. Stoll, K. Iribarren, J. Michels et al., "Calreticulin expression: interaction with the immune infiltrate and impact on survival in patients with ovarian and non-small cell lung cancer," OncoImmunology, vol. 5, no. 7, article e1177692, 2016.

[43] T. K. Eisenstein, B. Bushnell, J. J. Meissler, N. Dalal, R. Schafer, and H. F. Havas, "Immunotherapy of a plasmacytoma with attenuated Salmonella," Medical Oncology, vol. 12, no. 2, pp. 103-108, 1995.

[44] G. Chen, D. P. Wei, L. J. Jia et al., "Oral delivery of tumor-targeting Salmonella exhibits promising therapeutic efficacy and low toxicity," Cancer Science, vol. 100, no. 12, pp. 2437-2443, 2009.

[45] M. Yun, S. Pan, S. N. Jiang et al., "Effect of Salmonella treatment on an implanted tumor (CT26) in a mouse model," Journal of Microbiology, vol. 50, no. 3, pp. 502-510, 2012.

[46] E. Choe, R. A. Kazmierczak, and A. Eisenstark, "Phenotypic evolution of therapeutic Salmonella enterica serovar Typhimurium after invasion of TRAMP mouse prostate tumor," MBio, vol. 5, no. 4, pp. e01182-e01114, 2014.

[47] A. Vendrell, M. J. Gravisaco, J. C. Goin et al., "Therapeutic effects of Salmonella typhi in a mouse model of T-cell lymphoma," Journal of Immunotherapy, vol. 36, no. 3, pp. 171-180, 2013.

[48] S. Grille, M. Moreno, A. Brugnini, D. Lens, and J. A. Chabalgoity, "A therapeutic vaccine using Salmonella-modified tumor cells combined with interleukin-2 induces enhanced antitumor immunity in B-cell lymphoma," Leukemia Research, vol. 37, no. 3, pp. 341-348, 2013.

[49] M. Zhao, M. Yang, H. Ma et al., "Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice," Cancer Research, vol. 66, no. 15, pp. 7647-7652, 2006.

[50] M. Zhao, M. Yang, X. M. Li et al., "Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 3, pp. 755-760, 2005.

[51] M. Zhao, J. Geller, H. Ma, M. Yang, S. Penman, and R. M. Hoffman, "Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer," Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 24, pp. 10170-10174, 2007.

[52] Y. Zhang, Y. Tome, A. Suetsugu et al., "Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice," Anticancer Research, vol. 32, no. 7, pp. 2501-2508, 2012.

[53] S. Miwa, S. Y. Yano, Y. Zhang et al., "Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice," Oncotarget, vol. 5, no. 16, pp. 7119-7125, 2014.

[54] K. Hayashi, M. Zhao, K. Yamauchi et al., "Systemic targeting of primary bone tumor and lung metastasis of high-grade osteosarcoma in nude mice with a tumor-selective strain of Salmonella typhymurium," Cell Cycle, vol. 8, no. 6, pp. 870-875, 2009.

[55] C. Nagakura, K. Hayashi, M. Zhao et al., "Efficacy of a genetically-modified Salmonella typhimurium in an orthotopic human pancreatic cancer in nude mice," Anticancer Research, vol. 29, no. 6, pp. 1873-1878, 2009.

[56] Y. Hiroshima, M. Zhao, Y. Zhang et al., "Comparison of efficacy of Salmonella typhimurium A1-R and chemotherapy on stem-like and non-stem human pancreatic cancer cells," Cell Cycle, vol. 12, no. 17, pp. 2774-2780, 2013.

[57] H. Kimura, L. Zhang, M. Zhao et al., "Targeted therapy of spinal cord glioma with a genetically modified Salmonella typhimurium," Cell Proliferation, vol. 43, no. 1, pp. 41-48, 2010.

[58] X. Y. Fu, J. M. Besterman, A. Monosov, and R. M. Hoffman, "Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens," Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 20, pp. 9345-9349, 1991.

[59] R. M. Hoffman, "Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts," Nature Reviews Cancer, vol. 15, no. 8, pp. 451-452, 2015.

[60] K. Igarashi, K. Kawaguchi, T. Kiyuna et al., "Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic," Cell Cycle, vol. 17, no. 6, pp. 801-809, 2018.

[61] K. Igarashi, K. Kawaguchi, T. Murakami et al., "Intraarterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model," Cell Cycle, vol. 16, no. 12, pp. 1164-1170, 2017.

[62] T. Murakami, K. Igarashi, K. Kawaguchi et al., "Tumortargeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug," Oncotarget, vol. 8, no. 5, pp. 8035-8042, 2017.

[63] R. M. Hoffman, "Patient-derived orthotopic xenograft (PDOX) models of melanoma," International Journal of Molecular Sciences, vol. 18, no. 9, 2017.

[64] K. Kawaguchi, K. Igarashi, T. Murakami et al., "Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model," Oncotarget, vol. 7, no. 52, pp. 85929-85936, 2016.

[65] K. Kawaguchi, K. Igarashi, T. Murakami et al., "Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide," Cell Cycle, vol. 16, no. 13, pp. 1288-1294, 2017.

[66] K. Kawaguchi, K. Igarashi, T. Murakami et al., "Tumortargeting Salmonella typhimurium A1-R sensitizes melanoma with a BRAF-V600E mutation to vemurafenib in a patient-derived orthotopic xenograft (PDOX) nude mouse model," Journal of Cellular Biochemistry, vol. 118, no. 8, pp. 2314-2319, 2017.

[67] M. Yamamoto, M. Zhao, Y. Hiroshima et al., "Efficacy of tumor-targeting Salmonella A1-R on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model," PLoS One, vol. 11, no. 8, article e0160882, 2016.

[68] T. Kiyuna, T. Murakami, Y. Tome et al., "High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib-resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft PDOX nude mouse model," Oncotarget, vol. 7, no. 22, pp. 33046-33054, 2016.

[69] T. Murakami, J. DeLong, F. C. Eilber et al., "Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft (PDOX) model," Oncotarget, vol. 7, no. 11, pp. 12783-12790, 2016.

[70] K. Igarashi, K. Kawaguchi, T. Kiyuna et al., "Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models," Biochemical and Biophysical Research Communications, vol. 497, no. 4, pp. 1055-1061, 2018.

[71] J. F. Toso, V. J. Gill, P. Hwu et al., "Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma," Journal of Clinical Oncology, vol. 20, no. 1, pp. 142-152, 2002.

[72] K. M. Broadway, S. Suh, B. Behkam, and B. E. Scharf, "Optimizing the restored chemotactic behavior of anticancer agent Salmonella enterica serovar Typhimurium VNP20009," Journal of Biotechnology, vol. 251, pp. 76-83, 2017.

[73] C. H. Lee, C. L. Wu, S. H. Chen, and A. L. Shiau, "Humoral immune responses inhibit the antitumor activities mediated by Salmonella enterica serovar choleraesuis," Journal of Immunotherapy, vol. 32, no. 4, pp. 376-388, 2009.

[74] S. Kurashige and S. Mitsuhashi, "Enhancing effects of minicells prepared from Salmonella typhimurium on anti-tumor immunity in sarcoma 180-bearing mice," Cancer Immunology Immunotherapy, vol. 14, no. 1, pp. 1-3, 1982.

[75] S. Kurashige, Y. Akuzawa, and S. Mitsuhashi, "Synergistic anti-suppressor effect of mini cells prepared from Salmonella typhimurium and mitomycin C in EL 4-bearing mice," Cancer Immunology Immunotherapy, vol. 19, no. 2, pp. 127-129, 1985.

[76] J. W. Tam, A. L. Kullas, P. Mena, J. B. Bliska, and A. W. M. van der Velden, "CD11b+ Ly6Chi Ly6G- immature myeloid cells recruited in response to Salmonella enterica serovar Typhimurium infection exhibit protective and immunosuppressive properties," Infection and Immunity, vol. 82, no. 6, pp. 2606-2614, 2014.

[77] S. Grille, M. Moreno, T. Bascuas et al., "Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect," Immunology, vol. 143, no. 3, pp. 428-437, 2014.

[78] T. X. Phan, V. H. Nguyen, M. T.-Q. Duong, Y. Hong, H. E. Choy, and J.-J. Min, "Activation of inflammasome by attenuated Salmonella typhimurium in bacteria-mediated cancer therapy," Microbiology and Immunology, vol. 59, no. 11, pp. 664-675, 2015.

[79] J. E. Kim, T. X. Phan, V. H. Nguyen et al., "Salmonella typhimurium suppresses tumor growth via the pro-inflammatory cytokine interleukin-1[beta]," Theranostics, vol. 5, no. 12, pp. 1328-1342, 2015.

[80] F. Avogadri, D. Mittal, F. Saccheri et al., "Intra-tumoral Salmonella typhimurium induces a systemic anti-tumor immune response that is directed by low-dose radiation to treat distal disease," European Journal of Immunology, vol. 38, no. 7, pp. 1937-1947, 2008.

[81] K. Li, S. Qu, X. Chen, Q. Wu, and M. Shi, "Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways," International Journal of Molecular Sciences, vol. 18, no. 2, 2017.

[82] C. H. Lee, C. L. Wu, and A. L. Shiau, "Toll-like receptor 4 mediates an antitumor host response induced by Salmonella choleraesuis," Clinical Cancer Research, vol. 14, no. 6, pp. 1905-1912, 2008.

[83] F. M. de Melo, C. J. M. Braga, F. V. Pereira et al., "Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10," Immunology & Cell Biology, vol. 93, no. 1, pp. 86-98, 2015.

[84] N. D. Leigh, G. Bian, X. Ding et al., "A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic lymphocytemediated tumor immunity," PLoS One, vol. 9, no. 1, article e85587, 2014.

[85] J. H. Zheng, V. H. Nguyen, S. N. Jiang et al., "Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin," Science Translational Medicine, vol. 9, no. 376, article eaak9537, 2017.

[86] L. Sfondrini, A. Rossini, D. Besusso et al., "Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer," The Journal of Immunology, vol. 176, no. 11, pp. 6624-6630, 2006.

[87] J. Bohnhorst, T. Rasmussen, S. H. Moen et al., "Toll-like receptors mediate proliferation and survival of multiple myeloma cells," Leukemia, vol. 20, no. 6, pp. 1138-1144, 2006.

[88] F. Avogadri, C. Martinoli, L. Petrovska et al., "Cancer immunotherapy based on killing of Salmonella-infected tumor cells," Cancer Research, vol. 65, no. 9, pp. 3920-3927, 2005.

[89] D. Kocijancic, S. Leschner, S. Felgner et al., "Therapeutic benefit of Salmonella attributed to LPS and TNF-[alpha] is exhaustible and dictated by tumor susceptibility," Oncotarget, vol. 8, no. 22, pp. 36492-36508, 2017.

[90] S. Leschner, K. Westphal, N. Dietrich et al., "Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-[alpha]," PLoS One, vol. 4, no. 8, article e6692, 2009.

[91] D. A. Shilling, M. J. Smith, R. Tyther et al., "Salmonella typhimurium stimulation combined with tumour-derived heat shock proteins induces potent dendritic cell anti-tumour responses in a murine model," Clinical & Experimental Immunology, vol. 149, no. 1, pp. 109-116, 2007.

[92] F. C. Stark, S. Sad, and L. Krishnan, "Intracellular bacterial vectors that induce [CD8.sup.+] T cells with similar cytolytic abilities but disparate memory phenotypes provide contrasting tumor protection," Cancer Research, vol. 69, no. 10, pp. 4327-4334, 2009.

[93] T. Liu and A. K. Chopra, "An enteric pathogen Salmonella enterica serovar Typhimurium suppresses tumor growth by downregulating CD44high and CD4T regulatory (Treg) cell expression in mice: the critical role of lipopolysaccharide and Braun lipoprotein in modulating tumor growth," Cancer Gene Therapy, vol. 17, no. 2, pp. 97-108, 2010.

[94] F. Fallarino, U. Grohmann, and P. Puccetti, "Indoleamine 2,3-dioxygenase: from catalyst to signaling function," European Journal of Immunology, vol. 42, no. 8, pp. 1932-1937, 2012.

[95] D. H. Munn, "Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation," Current Opinion in Immunology, vol. 18, no. 2, pp. 220-225, 2006.

[96] D. Hurley, M. P. McCusker, S. Fanning, and M. Martins, "Salmonella-host interactions--modulation of the host innate immune system," Frontiers in Immunology, vol. 5, p. 481, 2014.

[97] O. H. Pham and S. J. McSorley, "Protective host immune responses to Salmonella infection," Future Microbiology, vol. 10, no. 1, pp. 101-110, 2015.

[98] Y. A. Yu, S. Shabahang, T. M. Timiryasova et al., "Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins," Nature Biotechnology, vol. 22, no. 3, pp. 313-320, 2004.

[99] F. Saccheri, C. Pozzi, F. Avogadri et al., "Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity," Science Translational Medicine, vol. 2, no. 44, article 44ra57, 2010.

[100] E. Oviedo-Orta and W. Howard Evans, "Gap junctions and connexin-mediated communication in the immune system," Biochimica et Biophysica Acta (BBA)--Biomembranes, vol. 1662, no. 1-2, pp. 102-112, 2004.

[101] H. Matsue, J. Yao, K. Matsue et al., "Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs," The Journal of Immunology, vol. 176, no. 1, pp. 181-190, 2006.

[102] A. J. Linley, M. Ahmad, and R. C. Rees, "Tumour-associated antigens: considerations for their use in tumour immunotherapy," International Journal of Hematology, vol. 93, no. 3, pp. 263-273, 2011.

[103] R. L. Santos and A. J. Baumler, "Cell tropism of Salmonella enterica," International Journal of Medical Microbiology, vol. 294, no. 4, pp. 225-233, 2004.

[104] J. Fensterle, B. Bergmann, C. L. R. P. Yone et al., "Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostatespecific antigen and cholera toxin subunit B," Cancer Gene Therapy, vol. 15, no. 2, pp. 85-93, 2008.

[105] I. Gentschev, J. Fensterle, A. Schmidt et al., "Use of a recombinant Salmonella enterica serovar Typhimurium strain expressing C-Raf for protection against C-Raf induced lung adenoma in mice," BMC Cancer, vol. 5, no. 1, 2005.

[106] K. Panthel, K. M. Meinel, V. E. Sevil Domenech et al., "Prophylactic anti-tumor immunity against a murine fibrosarcoma triggered by the Salmonella type III secretion system," Microbes and Infection, vol. 8, no. 9-10, pp. 2539-2546, 2006.

[107] E. Roider, S. Jellbauer, B. Kohn et al., "Invasion and destruction of a murine fibrosarcoma by Salmonella-induced effector CD8 T cells as a therapeutic intervention against cancer," Cancer Immunology, Immunotherapy, vol. 60, no. 3, pp. 371-380, 2011.

[108] H. Nishikawa, E. Sato, G. Briones et al., "In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines," The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1946-1954, 2006.

[109] S. Jellbauer, K. Panthel, J. H. Hetrodt, and H. Russmann, "CD8 T-cell induction against vascular endothelial growth factor receptor 2 by Salmonella for vaccination purposes against a murine melanoma," PLoS One, vol. 7, no. 4, p. e34214, 2012.

[110] W. Yoon, J. H. Choi, S. Kim, and Y. K. Park, "Engineered Salmonella typhimurium expressing E7 fusion protein, derived from human papillomavirus, inhibits tumor growth in cervical tumor-bearing mice," Biotechnology Letters, vol. 36, no. 2, pp. 349-356, 2014.

[111] H. Echchannaoui, M. Bianchi, D. Baud, M. Bobst, J. C. Stehle, and D. Nardelli-Haefliger, "Intravaginal immunization of mice with recombinant Salmonella enterica serovar Typhimurium expressing human papillomavirus type 16 antigens as a potential route of vaccination against cervical cancer," Infection and Immunity, vol. 76, no. 5, pp. 1940-1951, 2008.

[112] B. J. Qian, F. Yan, N. Li et al., "MTDH/AEG-1-based DNA vaccine suppresses lung metastasis and enhances chemosensitivity to doxorubicin in breast cancer," Cancer Immunology, Immunotherapy, vol. 60, no. 6, pp. 883-893, 2011.

[113] C. Jin, X. Duan, Y. Liu et al., "T cell immunity induced by a bivalent Salmonella-based CEACAM6 and 4-1BBL vaccines in a rat colorectal cancer model," Oncology Letters, vol. 13, no. 5, pp. 3753-3759, 2017.

[114] M. Loeffler, G. Le'Negrate, M. Krajewska, and J. C. Reed, "Attenuated Salmonella engineered to produce human cytokine LIGHT inhibit tumor growth," Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 31, pp. 12879-12883, 2007.

[115] M. Loeffler, G. Le'Negrate, M. Krajewska, and J. C. Reed, "IL18-producing Salmonella inhibit tumor growth," Cancer Gene Therapy, vol. 15, no. 12, pp. 787-794, 2008.

[116] B. S. Sorenson, K. L. Banton, N. L. Frykman, A. S. Leonard, and D. A. Saltzman, "Attenuated salmonella typhimurium with IL-2 gene reduces pulmonary metastases in murine osteosarcoma," Clinical Orthopaedics and Related Research, vol. 466, no. 6, pp. 1285-1291, 2008.

[117] B. S. Sorenson, K. L. Banton, N. L. Frykman, A. S. Leonard, and D. A. Saltzman, "Attenuated Salmonella typhimurium with interleukin 2 gene prevents the establishment of pulmonary metastases in a model of osteosarcoma," Journal of Pediatric Surgery, vol. 43, no. 6, pp. 1153-1158, 2008.

[118] C. Agorio, F. Schreiber, M. Sheppard et al., "Live attenuated Salmonella as a vector for oral cytokine gene therapy in melanoma," The Journal of Gene Medicine, vol. 9, no. 5, pp. 416-423, 2007.

[119] M. Loeffler, G. le'Negrate, M. Krajewska, and J. C. Reed, "Inhibition of tumor growth using Salmonella expressing Fas ligand," Journal of the National Cancer Institute, vol. 100, no. 15, pp. 1113-1116, 2008.

[120] W. S. Yoon, Y. S. Chae, J. Hong, and Y. K. Park, "Antitumor therapeutic effects of a genetically engineered Salmonella typhimurium harboring TNF-[alpha] in mice," Applied Microbiology and Biotechnology, vol. 89, no. 6, pp. 1807-1819, 2011.

[121] H. D. Cao, Y. X. Yang, L. Lu et al., "Attenuated Salmonella typhimurium carrying TRAIL and VP3 genes inhibits the growth of gastric cancer cells in vitro and in vivo," Tumori Journal, vol. 96, no. 2, pp. 296-303, 2010.

[122] R. Germanier and E. Fiirer, "Isolation and characterization of Gal E mutant Ty 21a of Salmonella typhi: a candidate strain for a live, oral typhoid vaccine," The Journal of Infectious Diseases, vol. 131, no. 5, pp. 553-558, 1975.

[123] J. Y. Wang, M. F. Pasetti, F. R. Noriega et al., "Construction, genotypic and phenotypic characterization, and immunogenicity of attenuated AguaBA Salmonella enterica serovar Typhi strain CVD 915," Infection and Immunity, vol. 69, no. 8, pp. 4734-4741, 2001.

[124] A. Vendrell, M. J. Gravisaco, M. F. Pasetti et al., "A novel Salmonella Typhi-based immunotherapy promotes tumor killing via an antitumor Th1-type cellular immune response and neutrophil activation in a mouse model of breast cancer," Vaccine, vol. 29, no. 4, pp. 728-736, 2011.

[125] A. Vendrell, C. Mongini, M. J. Gravisaco et al., "An oral Salmonella-based vaccine inhibits liver metastases by promoting tumor-specific T-cell-mediated immunity in celiac and portal lymph nodes: a preclinical study," Frontiers in Immunology, vol. 7, p. 72, 2016.

[126] S. Domingos-Pereira, R. Hojeij, E. Reggi et al., "Local Salmonella immunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor," OncoImmunology, vol. 4, no. 7, article e1016697, 2015.

[127] A. G. Niethammer, H. Lubenau, G. Mikus et al., "Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-receptor 2 in patients with stage IV and locally advanced pancreatic cancer," BMC Cancer, vol. 12, no. 1, p. 361, 2012.

[128] F. H. Schmitz-Winnenthal, N. Hohmann, A. G. Niethammer et al., "Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: a randomized, placebo-controlled, phase 1 trial," OncoImmunology, vol. 4, no. 4, article e1001217, 2015.

[129] A. Le Gouellec, X. Chauchet, B. Polack, L. Buffat, and B. Toussaint, "Bacterial vectors for active immunotherapy reach clinical and industrial stages," Human Vaccines & Immunotherapeutics, vol. 8, no. 10, pp. 1454-1458, 2012.

[130] W. B. Coley, "The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus)," Proceedings of the Royal Society of Medicine, vol. 3, pp. 1-48, 1910.

[131] D. M. Wall, C. V. Srikanth, and B. A. McCormick, "Targeting tumors with salmonella Typhimurium- potential for therapy," Oncotarget, vol. 1, no. 8, pp. 721-728, 2010.

[132] P. Lehouritis, C. Springer, and M. Tangney, "Bacterial-directed enzyme prodrug therapy," Journal of Controlled Release, vol. 170, no. 1, pp. 120-131, 2013.

[133] D. M. Heimann and S. A. Rosenberg, "Continuous intravenous administration of live genetically modified Salmonella typhimurium in patients with metastatic melanoma," Journal of Immunotherapy, vol. 26, no. 2, pp. 179-180, 2003.

[134] J. Nemunaitis, C. Cunningham, N. Senzer et al., "Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients," Cancer Gene Therapy, vol. 10, no. 10, pp. 737-744, 2003.

[135] K. L. Roland and K. E. Brenneman, "Salmonella as a vaccine delivery vehicle," Expert Review of Vaccines, vol. 12, no. 9, pp. 1033-1045, 2013.

[136] M. O. Din, T. Danino, A. Prindle et al., "Synchronized cycles of bacterial lysis for in vivo delivery," Nature, vol. 536, no. 7614, pp. 81-85, 2016.

[137] R. Luria-Perez, L. Cedillo-Barron, L. Santos-Argumedo, V. F. Ortiz-Navarrete, A. Ocana-Mondragon, and C. R. Gonzalez-Bonilla, "A fusogenic peptide expressed on the surface of Salmonella enterica elicits CTL responses to a dengue virus epitope," Vaccine, vol. 25, no. 27, pp. 5071-5085, 2007.

[138] P. E. Massa, A. Paniccia, A. Monegal, A. de Marco, and M. Rescigno, "Salmonella engineered to express CD20targeting antibodies and a drug-converting enzyme can eradicate human lymphomas," Blood, vol. 122, no. 5, pp. 705-714, 2013.

[139] C. Pinero-Lambea, G. Bodelon, R. Fernandez-Perianez, A. M. Cuesta, L. Alvarez-Vallina, and L. A. Fernandez, "Programming controlled adhesion of E. coli to target surfaces, cells, and tumors with synthetic adhesins," ACS Synthetic Biology, vol. 4, no. 4, pp. 463-473, 2015.

Marco Antonio Hernandez-Luna (ID) (1) and Rosendo Luria-Perez (ID) (2)

(1) Department of Medicine and Nutrition, University of Guanajuato, Campus Leon, Leon, GTO, Mexico

(2) Unit of Investigative Research on Oncological Diseases, Children's Hospital of Mexico Federico Gomez, Mexico City, Mexico

Correspondence should be addressed to Rosendo Luria-Perez;

Received 28 April 2018; Revised 9 July 2018; Accepted 26 July 2018; Published 13 September 2018

Academic Editor: Zenghui Teng

Caption: Figure 1: Oncolytic activity of Salmonella enterica. Once Salmonella reaches the tumor microenvironment, it promotes tumor cell elimination through several mechanisms: (A) inhibits tumor angiogenesis mediated by suppressing HIF-1[alpha] transcription factor of VEGF; (B) decreases AKT and mTOR phosphorylation, avoiding possible activation of HIF- 1[alpha], thus increases Beclin and LC3, two proteins required for autophagy; (C) degradation of nitrites and nitrates by the enzyme nitrite reductase (NirB) of Salmonella enterica, generates nitric oxide (NO) an apoptotic agent.

Caption: Figure 2: Activation of innate and adaptive immune response in the tumor microenviroment by Salmonella enterica. Once Salmonella colonizes tumor tissue, it induces an antitumor innate and adaptive immune response through several mechanisms: (a) promotes proinflammatory cytokines (IFN-[gamma] and TNF-[alpha]), while decreases both anti-inflammatory (TGF-[beta], IL-4) and angiogenic factors (VEGF) associated with tumor growth progression; (b) interactions between bacterial components (LPS and flagellin) and tumor cell receptors as TLR4 or TLR5, respectively, induce cytokine secretions that promotes the recruitment of neutrophils, macrophages, T lymphocytes, B lymphocytes, and dendritic cells to the tumor microenvironment; (c) Salmonella colonization induces the expression of connexin 43; this molecule plays a major role in the cross-presentation of tumor antigens by DCs to [CD8.sup.+] T- cells; (d) the presence of antitumor [CD4.sup.+] T-cell induce the activation and differentiation of B lymphocytes into plasma cells, producing specific antitumor antibodies.
Table 1: Antitumoral intrinsic activity of Salmonella

Specie             Strain              Mutation

Salmonella         SI4028        pur: ilv; arg; ura;
Typhimurium                              aro

Salmonella     SL7207 SL1344     aroA, hisG46; cheY;
Typhimurium                      fliGHI; invG; phoP;
                                  sseD; ssrB; pur A

Salmonella         SL3235                aroA

Salmonella        VNP20009            purl, msbB

Salmonella     Wild-type LT2       hppGpp hisD2550,
Typhimurium                       rpoS, aroA, rfaH,

Salmonella    14028 auxotrophy         Leu, Arg
Typhimurium     A1 and Al-R

Salmonella         LVR01                 aroC

Salmonella         CVD915               guaBA


Salmonella Typ      Al-R               Leu, Arg

Phase I

Salmonella        VNP20009            purl, msbB

Specie         Tumor-bearing mice       Administration

Salmonella          Melanoma          Intraperitoneally

Salmonella        Colon cancer          Intravenously,
Typhimurium                           intraperitoneally

Salmonella        Plasmocytoma        Intraperitoneally

Salmonella          Melanoma               Orally,
Typhimurium                           intraperitoneally

Salmonella      Prostate cancer       Intraperitoneally

                Prostate cancer        Intra tumorally,

                 Breast cancer          Intravenously

Salmonella     Breast cancer bone       Intravenously
Typhimurium     metastasis Bone         Intravenously
                 tumor and lung
                 metastasis of

               Pancreatic cancer      Intraperitoneally,
                                       Intra tumorally

               Spinal cord glioma       Intravenously

Salmonella      B-cell lymphoma        Intra tumorally

Salmonella      T-cell lymphoma        Intra tumorally,
Typhi                                   subcutaneously

PDOX              Osteosarcoma          Intravenously
Models             metastasis

                  Osteosarcoma          Intratumorally

Salmonella         Melanoma                Orally
Typ                                     Intravenously
              Follicular dendritic    Intraperitoneally
                  cell sarcoma

              Soft tissue sarcoma       Intratumorally
Phase I

Salmonella    Metastasic melanoma       Intravenously

Specie         Reference

Salmonella        [14]

Salmonella        [30]

Salmonella        [43]

Salmonella        [44]

Salmonella        [46]

                [50, 51]


Salmonella     [53] [54]

                [55, 56]


Salmonella        [48]

Salmonella        [47]

PDOX              [60]


Salmonella        [64]
Typ             [65-67]

Phase I

Salmonella        [71]

Table 2: Salmonella enterica as delivery system of TAA/TSA
and immunomodulatory molecules.

Species         Mutations      Heterologous     Tumor-bearing mice

Tumor-associated antigens or tumor-specific antigens (TAA/TSA)

                  aroA          Antigen PSA      Prostate cancer

                  aroA            L1HPV16        Cervical cancer

Salmonella     aroA, sptP     Antigen p60217       Fibrosarcoma
Typhimurium                     225 VEGFR-2          Melanoma

              aroA, hisG46         C-Raf           Lung adenoma

               aroA, aroD     SipB160-HPV16E7    Cervical cancer

Salmonella     phoP, phoQ        NY-ESO-1            Sarcoma

Salmonella      dam, aroA       MTDH/AEG1-1     Breast cancer and
Typhimurium                                         metastasis

Immunomodulatory and apoptosis inductor molecules

                                   CCL21         Colon and breast

Salmonella     purl, msbB       LIGHT IL-18      Colon and breast
Typhimurium                                      cancer Colon and
                                                  breast cancer

                                   FasL          Colon and breast

Salmonella    cya, crp, asd        IL-2          Osteosarcoma and
Typhimurium                                         metastasis

                  aroA        IL-4 and IL-18         Melanoma

Salmonella    aroA, hisG46         TRAIL          Gastric cancer

               aroA, aroD       TNF[alpha]           Melanoma

Clinical Trial Phase I

Salmonella        galE            VEGFR-2       Pancreatic cancer

Species         Mutations     Antitumoral response      Reference

Tumor-associated antigens or tumor-specific antigens (TAA/TSA)

                  aroA             Cytotoxic              [104]
                               [CD8.sup.+] T-cell

                  aroA        IFN-[gamma] and TNF-        [111]
                               [alpha] secretion

Salmonella     aroA, sptP     Effector and memory      [106, 107]
Typhimurium                   [CD8.sup.+] T-cells         [109]
                              Specific CD8 T-cell

              aroA, hisG46     Humoral and T-cell         [105]

               aroA, aroD       Humoral response          [110]

Salmonella     phoP, phoQ      NY-ESO-1-specific          [108]
Typhimurium                    [CD8.sup.+] T-cell

Salmonella      dam, aroA      [CD8.sup.+] T-cell         [112]
Typhimurium                         response

Immunomodulatory and apoptosis inductor molecules

                                [CD4.sup.+] and            [33]
                               [CD8.sup.+] T-cell

Salmonella     purl, msbB       Infiltration of        [114] [115]
Typhimurium                    inflammatory cells
                               [CD4.sup.+] T-cell
                                response and NK

                                Accumulation of           [119]

Salmonella    cya, crp, asd         NK cells            [116, 117]

                  aroA         Increase levels of         [118]

Salmonella    aroA, hisG46     Increase levels of         [121]
Typhimurium                     caspases 3 and 9

               aroA, aroD           NK cells              [120]

Clinical Trial Phase I

Salmonella        galE          T-cell response         [127, 128]

CCL21: chemokine (C-C motif) ligand 21; C-Rafl: serine-threonine
kinases of the Raf family; FasL: Fas ligand; IL-2: interleukin-2;
IL-4: interleukin-4; IL-18: interleukin-18; LIGHT: a member of TNF
cytokine family; L1HPV16: capsid protein L1HPV16; MTDH: metadherin;
NY-ESO-1: testis antigen; PSA: prostate-specific antigen; HPV16E7:
human papillomavirus protein E7; TRAIL: TNF-related
apoptosis-inducing ligand; TNF-[alpha]: tumor necrosis factor a;
VEGFR-2: vascular endothelial growth factor receptor-2; NK: natural
killer; IFN-[gamma]: interferon [gamma].
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Author:Hernandez-Luna, Marco Antonio; Luria-Perez, Rosendo
Publication:Journal of Immunology Research
Date:Jan 1, 2018
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