Immune-checkpoint inhibitors and vaccines support the immunostimulatory theory of cancer

MONTAGNA, DANIELA R.; RUGGIERO, RAÚL A.; CHIARELLA, PAULA; VERMEULEN, MÓNICA; STRAZZA, ARIEL R.

Congreso; Reunión Conjunta de Sociedades de Biociencia; 2017

IMMUNE-CHECKPOINT INHIBITORS AND ANTI-TUMOR VACCINES SUPPORT THE IMMUNOSTIMULATORY THEORY OF CANCERPaula Chiarella; Daniela Montagna; Ariel Strazza; Mónica Vermeulen and Raúl RuggieroImmune-checkpoint inhibitors and antitumor vaccines produce tumor-inhibitory and stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment was initiated. These paradoxical results can be understood by the immunosurveillance postulates but might be explained by the Immune Stimulatory Theory of Cancer, that was originally proposed on the basis that the immune response (IR) induced by immunogenic murine tumors was not monotonic but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. In a previous work we have demonstrate that most spontaneous murine tumors (ST) studied grow in an accelerated way in pre-immunized hosts and more in immunodepressed mice; that the interaction of specifically-immune T cells and target tumor cells at low stimulatory ratios enhanced the production of rantes and MIP1α and when Winn tests were carried out in indomethacin-treated tumor bearing mice or TLR4KO tumor bearing mice, the stimulatory effect was not observed. We extended those observations to understand better the mechanism. We observed in ST an increase of PDL1 and an activation of TLR4 and p38 signaling pathways, which recruit more macrophages and other inflammatory cells that would produce pro-inflammatory cytokines, TNFα (p