ON THE MECHANISMS UNDERLYING THE IMMUNOSTIMULATORY THEORY OF CANCER

CHIARELLA P, VULCANO M, BRUZZO J, VERMEULEN M, VANZULLI S, MAGLIOCO A, CAMERANO; DANIELA MONTAGNA; MÓNICA VERMEULEN; LUCIANA BALBOA; GRACIELA DRAN; ROBERTO MEISS; RAÚL RUGGIERO

Medellin

Congreso; INMUNOCOLOMBIA; 2015

ALAI

There is a rather generalized belief that the worst possible outcome for the application of immunological therapies against cancer is a null effect on tumor growth. However, a significant body of evidence, summarized in the immunostimulatory theory of cancer suggests that, upon certain circumstances, the growth of tumors can be accelerated, rather than inhibited, by the specific immune response designed to attack the tumor. In this work, we have confirmed and extended the empirical basis of the immunostimulatory theory demonstrating that the immune response evoked by strongly immunogenic chemically-induced and apparently non-immunogenic spontaneous murine tumors is biphasic, with weak immune responses inducing stimulation while strong immune responses inducing inhibition of tumor growth. In line with the above observations, we could also demonstrate that most spontaneous murine tumors grow in an accelerated way in pre-immunized hosts and grow more slowly - instead of faster as strongly immunogenic tumors do - in immunodepressed mice. These results do not fall in easily with a linear and monotonic IRC but is consistent with the biphasic IRC postulated by the immunostimulatory theory. Our experiments also revealed that a weak T-dependent anti-tumor immune response could not explain by itself the phenomenon of tumor-immunostimulation. However, the interaction of immune cells (but not naïve cells or cells immune to another tumor) and target tumor cells at a low ratio induced the production of some chemokines, such as RANTES and MIP-1α, which recruited resident macrophages to the tumor site which in turn upon TLR4 activation would recruit more macrophages and other inflammatory cells which might produce growth-stimulating signals for the residual tumor cells. In addition, attempts to treat established tumors displaying weak or strong immunogenicity by immunological schedules demonstrated that anti-tumor vaccines may produce inhibitory, null or stimulatory effects on tumor growth depending upon the antigenic profile of the tumor, the immunogenic strength of the vaccine used, and the immunological state of the host.