Therapeutic Effects of Salmonella Typhi in a Mouse Model of T-Cell Lymphoma

Abstract

In this study, we assessed the effectiveness of a live, attenuated Salmonella enterica serovar Typhi (S. Typhi) vaccine strain as a cancer immunotherapy in a mouse model of metastatic T-cell lymphoma. EL4 tumor-bearing C57BL/6J mice immunized with S. Typhi strain CVD 915, by injection into the tumor and the draining lymph node areas, displayed a significant decrease in tumor growth, a reduction in the mitotic index (MI) of tumors, a delayed development of palpable lymph node metastases and most importantly improved survival, compared to untreated mice. Besides, complete tumor regression was achieved in a small number of bacteria-treated mice. A successful therapeutic response associated with a significant reduction of tumor mass was evident as early as 5 days after treatment. The administration of Salmonella to tumor-bearing mice promoted early cellular infiltration (mainly neutrophils) within the tumor, and was accompanied by a decreased intratumoral interleukin 10 production as well as by leukocyte expansion in tumor draining lymph nodes. A tumor-specific memory immune response was induced in most of cured animals, as evidenced by the lack of tumor growth after a rechallenge with the same tumor. EL4 cells cultured with live Salmonella failed to proliferate and underwent apoptosis in a dose-dependent, time-dependent, and contact-dependent manner. To our knowledge, these results demonstrate for the first time the efficacy of a S. Typhi vaccine strain as an oncolytic and immunotherapeutic agent against a highly malignant tumor and support the use of S. Typhi-based vaccine strains in cancer therapy.

Potential therapeutic anti-tumor effect of aSalmonella-based vaccine

“…5 Likewise, Salmonella typhi-based immunotherapy reportedly mediated tumor-specific immune responses in tumor-draining LNs, with an associated reduction in the number of Tregs among the CD4 + T cell population. 8 In our recently reported study, we also found that the percentage of CD25 + FoxP3 + Tregs among the CD4 + T cell population was significantly reduced in tumor-bearing mice intratumorally treated with RASV, compared with PBStreated controls 15 (Fig. 3).…”

Exosomes Isolated from Ascites of T-Cell Lymphoma-Bearing Mice Expressing Surface CD24 and HSP-90 Induce a Tumor-Specific Immune Response

“…IFN-γ levels were measured in culture supernatants by enzyme-linked immunosorbent assays (ELISA) using a commercial kit (eBioscience) following the manufacturer’s instructions. Samples were read at 492 nm (31). …”

The delicate balance in genetically engineering live vaccines

“…Vendrell et al [61;62] have described in two recent studies, encouraging results using an engineered S . Typhi attenuated vaccine candidate as a therapeutic intervention to promote tumor reduction when injected directly into the tumor and surrounding draining lymph nodes.…”

“…Typhi attenuated vaccine candidate as a therapeutic intervention to promote tumor reduction when injected directly into the tumor and surrounding draining lymph nodes. This approach was used in mouse models of breast cancer [61] and T-cell lymphoma [62], and in both cases resulted in significant infiltration of activated neutrophils not observed with untreated tumors. A reduction in invasion of tumor cells into nearby tissue, along with a reduction of potentially immunosuppressive T reg cells into the draining lymph nodes, accompanied delayed development of metastases and increased survival times in both studies as well.…”

“…In the case of immunotherapy against the mammary adenocarcinoma, significant infiltration of neutrophils was observed in necrotic areas that formed micro-abscesses [61]. Remarkably, immunotherapy with the metastatic T-cell lymphoma resulted in complete tumor regression in 10% of treated animals (3 out of 30 treated), which engendered tumor-specific immunity when rechallenged with the homologous tumor (in 2 of the 3 re-challenged animals) [62]. Interestingly, although the attenuated vaccine strain was engineered to be dependent on guanine for growth, viable organisms were recovered from tumor tissues for up to 7 days after injection in both studies; it was hypothesized that a nutrient-rich environment required by a rapidly growing tumor might provide just enough benefit to vaccine organisms to enhance persistence, which could theoretically enhance antitumor inflammatory responses and promote tumor-specific cytotoxicity either directly or indirectly.…”