Abstract
A major obstacle for the development of effective immunotherapy is the ability of tumors to escape the immune system. The possibility to kill tumor cells because they are recognized as infected rather than as malignant could help overcome immune escape mechanisms. Here we report a conceptually new approach of cancer immunotherapy based on in vivo infection of tumors and killing of infected tumor cells. Attenuated but still invasive, Salmonella typhimurium can be successfully exploited to invade melanoma cells that can present antigenic determinants of bacterial origin and become targets for anti-Salmonella-specific T cells. However, to fully appreciate the anticancer therapeutic properties of S. typhimurium, tumor-bearing mice need to be vaccinated against S. typhimurium before intratumoral Salmonella injection. Tumor infection when coupled to anti-Salmonella vaccination leads to 50% to 100% tumor-free mice with a better outcome on larger tumors. Invasive Salmonella also exert an indirect toxic effect on tumor cells through the recruitment of inflammatory cells and the cross-presentation of tumor antigens, which allow induction of tumor-specific immune response. This is effective in retarding the growth of untreated established distant tumors and in protecting the mice from subsequent tumor challenges.
Highlights
It has become apparent that despite the great specificity achieved with immunotherapy against cancers, a single modality is insufficient to eradicate such a complex disease [1]
To verify that the red S. typhimurium were inside the tumor cells, nonpermeabilized cells were stained with FITC anti-Salmonella antibody, which was accessible only to extracellular bacteria
We show that invasive S. typhimurium SL1344wt were able to infect tumor cells; by contrast, noninvasive S. typhimurium InvA were unable to efficiently invade tumor cells and stained in yellow (Fig. 1A, middle, due to the colocalization of red and green staining)
Summary
It has become apparent that despite the great specificity achieved with immunotherapy against cancers, a single modality is insufficient to eradicate such a complex disease [1]. Many approaches have been developed to induce immunity against cancer and remarkably potent antitumor-specific cytotoxic responses have been achieved [2,3,4,5]. A number of studies have shown that it is possible to increase the visibility of the tumor by inducing an inflammatory state within the tumor microenvironment. This can be achieved by subjecting the tumor area to irradiation [6], radiofrequency ablation [13], or by injecting bacterial products like CpG containing DNA [14] or directly anaerobic bacteria such as Clostridium spp. This can be achieved by subjecting the tumor area to irradiation [6], radiofrequency ablation [13], or by injecting bacterial products like CpG containing DNA [14] or directly anaerobic bacteria such as Clostridium spp. [15]
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