Salmonella vaccine carrier strains: effective delivery system to trigger anti-tumor immunity by oral route

Abstract

Recombinant Salmonella strains expressing heterologous antigens can be delivered by oral route triggering the elicitation of efficient antigen-specific humoral, T helper and cytotoxic responses. The potential of attenuated Salmonella spp. to trigger anti-tumor immunity was evaluated for the first time by using beta-galactosidase (beta-gal) as a model tumor-associated antigen (TAA). Beta-gal was expressed in a Salmonella typhimurium aroA vaccine carrier strain either constitutively or under the control of a promoter activated upon infection. Oral immunization with both vaccine prototypes resulted in the elicitation of beta-gal-specific humoral and cell-mediated immunity. Although both strains were able to trigger antigen-specific CTL, responses were more efficient when the expression was controlled by the promoter activated upon infection. The anti-tumor efficacy of the stimulated response was validated by challenging vaccinated animals with an aggressive fibrosarcoma transfected with beta-gal, which operationally acts as a TAA. Both groups of vaccinated mice exhibited a significant reduction in tumor take and growth with respect to animals vaccinated with plasmidless carrier (p < 0.05). However, the overall efficiency was better in the group in which beta-gal was controlled by the in vivo-activated promoter (85% versus 54%; p < 0.05).

Listeria monocytogenesas a vector for tumor-associated antigens for cancer immunotherapy

“…Several different Salmonella strains have been used as vaccine vectors, primarily targeting mucosal immunity [7][8][9]. Salmonella can be used as an oral vaccine, which can cross the gut epithelial barrier and be taken up by macrophages and other phagocytes [9].…”

“…Salmonella vectors have also been studied to determine their antitumor efficacy and the extent to which they can stimulate an immune response. This vector has demonstrated some antitumor efficacy and the generation of antigen-specific tumor responses in treated mice [7,8,10]. Through the use of L. monocytogenes vectors, highly specific immune responses can be generated.…”

Prophylactic anti-tumor immunity against a murine fibrosarcoma triggered by the Salmonella type III secretion system

“…Some former studies have focused on the use of L. monocytogenes for this purpose [23] taking advantage of Listeria's escape into the host cell cytoplasm, thus promoting MHC class I-restricted immune responses. For the first time, Medina et al presented data demonstrating that attenuated Salmonella expressing a tumor-associated antigen also constitute a promising tool for the immunoprohylaxis of tumors [24]. In addition, Salmonella is particularly appealing as a cancer therapeutic agent because this bacterial species is able to colonize preferentially tumors and because it has an intrinsic anticancer property [25,26].…”

Modulation of host immune responses stimulated bySalmonella vaccine carrier strains by using different promoters to drive the expression of the recombinant antigen

“…In fact, we have previously reported that attenuated Salmonella expressing TAA can be exploited for the generation of anti-tumor responses [18].…”

“…We have recently shown that immunization of mice with Salmonella carrier strains expressing a tumor-associated antigen (TAA) decreased the development of local tumor compared to non-immunized mice [18]. Here, we determined whether the potential of modulating the immune response stimulated by Salmonella-based vaccine prototypes can be exploited to achieve a better control of the hematogenous spread of tumor cells, thereby preventing the establishment of metastatic tumors.…”