Improvement of Antitumor Therapies Based on Vaccines and Immune-Checkpoint Inhibitors by Counteracting Tumor-Immunostimulation

CHIARELLA, PAULA; VERMEULEN, MÓNICA; MONTAGNA, DANIELA R.; VALLECORSA, PABLO; STRAZZA, ARIEL RAMIRO; MEISS, ROBERTO P.; BUSTUOABAD, OSCAR D.; RUGGIERO, RAÚL A.; PREHN, RICHMOND T.

Frontiers in Oncology

Frontiers

Año: 2018 vol. 8

Immune-checkpoint inhibitors and antitumor vaccines may produce both tumorinhibitoryand tumor-stimulatory effects on growing tumors depending on the stageof tumor growth at which treatment is initiated. These paradoxical results are notnecessarily incompatible with current tumor immunology but they might better beexplained assuming the involvement of the phenomenon of tumor immunostimulation.This phenomenon was originally postulated on the basis that the immune response(IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic,with strong IR producing inhibition and weak IR inducing stimulation of tumorgrowth. Herein, we extended those former observations to weak spontaneous murinetumors growing in pre-immunized, immune-competent and immune-depressed mice.Furthermore, we demonstrated that the interaction of specifical T cells and targettumor cells at low stimulatory ratios enhanced the production of chemokines aimedto recruit macrophages at the tumor site, which, upon activation of toll-like receptor4 and p38 signaling pathways, would recruit and activate more macrophages andother inflammatory cells which would produce growth-stimulating signals leading to anaccelerated tumor growth. On this basis, the paradoxical effects achieved by immunologicaltherapies on growing tumors could be explained depending upon where thetherapy-induced IR stands on the biphasic IR curve at each stage of tumor growth.At stages where tumor growth was enhanced (medium and large-sized tumors),counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategiesor, more efficiently, with selective inhibitors of p38 signaling pathways enabled theotherwise tumor-promoting immunological strategies to produce significant inhibitionof tumor growth.