Intra‐tumoral Salmonella typhimurium induces a systemic anti‐tumor immune response that is directed by low‐dose radiation to treat distal disease

Abstract

Salmonella typhimurium is a facultative anaerobic bacterium able to multiply preferentially in tumors and inhibit their growth. The mechanisms through which Salmonella exerts its anti-cancer properties are not fully understood. We recently showed that intra-tumoral Salmonella injection results not only in the regression of even bulky tumor masses, but also impacts on the growth of distant untreated lesions. Here we describe how Salmonella exerts its systemic anti-cancer effects and means to potentiate them. The outburst of an early inflammatory reaction in the treated tumor promotes the development of an immunostimulatory cytokine environment both locally and in the draining lymph node. Within the next 10 days, an efficient cross-presentation of endogenous tumor antigens by dendritic cells at the tumor-draining lymph node leads to the priming of effective anti-tumor CD8 + T cell responses. This potentially broadly reactive T cell repertoire can be directed to other pre-established melanomas by low-dose radiotherapy enhancing the Salmonella anticancer effect. We demonstrate that Salmonella-based therapy coupled to low-dose radiotherapy dampens tumor immune escape mechanisms at different levels and allows controlling systemic disease in a CD8 + T cell-dependent manner.

Treatment Failure of a TLR-7 Agonist Occurs Due to Self-Regulation of Acute Inflammation and Can Be Overcome by IL-10 Blockade

“…However, tumors grew back after treatment withdrawal. These studies demonstrate that imiquimod therapy not only stimulates proinflammatory cytokines and augments Agspecific CD8 + T cells, but also stimulates the proliferation of The observation that acute inflammation can lead to tumor destruction has been previously reported for a variety of local treatments, such as intratumoral bacterial/viral injection, cytokine injection, and cryoablation (27)(28)(29). All of these treatments have been shown to induce intratumor inflammation that favors crosspriming of tumor Ags and upregulation of MHC I.…”

Immunological mechanism of low-dose priming radiation resistance in walker-256 tumor model mice

“…The results of the present study, which demonstrated that a low-dose of priming radiation was able to trigger the NK cytotoxic function, suggested that the therapeutic efficacy may be increased by the augmentation of NK cytotoxic function. The present and previous study results confirmed that stimulation of the antineoplastic immune surveillance was mediated by NK lymphocytes, at least partially, and the accumulating experimental evidence indicated that low-level exposure to low LET radiation inhibited tumor development (21,22).…”

Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas

“…The efficacy of Salmonella to target and eradicate growing tumors has been well documented. 2,4,5 However, colonization and persistence of Salmonella within healthy tissues weaken its therapeutic efficacy and causes undesirable adverse effects. 3,26 Therefore, it became necessary to develop novel methods to boost the tumor tropism of Salmonella.…”

“…4,5 Colony-forming units (cfus) were determined for each transformant with or without isopropyl-L-thio-beta-Dgalactopyranoside induction and were verified after each experiment.…”

“…3 Our group, 4,5 among others, 6,7 has previously demonstrated that Salmonella can eradicate tumors in mouse models. Indeed, intratumoral injection of Salmonella into aggressive melanomas has led to tumor regression and rejection.…”