ON THE MECHANISMS UNDERLYING THE IMMUNOSTIMULATORY THEORY OF CANCER

PAULA CHIARELLA; DANIELA MONTAGNA; MÓNICA VERMEULEN; LUCIANA BALBOA; GRACIELA DRAN; ROBERTO MEISS; RAÚL RUGGIERO

Congreso; IMMUNOCOLOMBIA 2015; 2015

11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología

Many years ago, Prehn proposed the immunostimulatory theory of cancer on the basis that the immune response (IR) evoked by strongly immunogenic chemically induced murine tumors was not monotonic -as the orthodoxy predicted- but biphasic, with weak IR inducing stimulation while strong IR inducing inhibition of tumor growth. In this work, we have extended these pioneer observations to spontaneous murine tumors. This generalization was supported by classical immunological tests and immune-checkpoint inhibitors and by the demonstration that most spontaneous murine tumors grow faster in pre-immunized hosts and more slowly - instead of faster as strongly immunogenic tumors do - in immunodepressed mice suggesting that they usually induce a weak and tumorstimulatoryIR. We also demonstrated that the interaction of specifically immune T cells(but not naïve cells or cells immune to another tumor) and target tumor cells at low stimulatory ratios enhanced the production of RANTES and MIP-1α, two chemokines involved in the recruitment of resident macrophages at the tumor site.In turn, these macrophages, upon activation of TLR4 and p38 and COX-2 signaling pathways, would recruit more macrophages and other inflammatory cells which might produce more growth-stimulating signals leading to an accelerated tumor growth. In line with these observations, attempts to treat established tumors with immunological schedules demonstrated that, although upon certain circumstances,anti-tumor vaccines and immune-checkpoint inhibitors may be inhibitory of tumor growth, in other cases, they may run a real risk of doing harm if the immunity induced by them is too weak to move the reaction beyond the tumor stimulatory part of the IR curve.