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

Paula Chiarella,Oscar D Bustuoabad,Mónica Vermeulen,Richmond T Prehn,Raúl A Ruggiero,Ariel Ramiro Strazza,Roberto P Meiss,Daniela R Montagna,Pablo Vallecorsa

doi:10.3389/fonc.2018.00006

Abstract

Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained 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 tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-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 strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.

Highlights

Since the classical work of Prehn and Main [1] demonstrating that vaccination against chemically induced murine tumors was feasible, there were numerous attempts to treat human tumors using immunological strategies
The absence of inhibitory-mediated immune effects against CEI and LB tumors could be associated, at least in part, with the fact that both tumors displayed high expression of programmed death-ligand 1 (PD-L1) that could prevent the onset of an inhibitory antitumor immune response (IR) (Figures 1F–H)
Supporting this contention, when Winn tests were carried out mixing CEI or LB tumor cells with spleen cells collected from mice immunized with X-lethaly irradiated tumor cells that had been pretreated with an inhibitor of PD-L1 expression (JQ1), a significant inhibition was detected at high ratios while the tumor-stimulating effect moved toward lower ratios

Summary

Introduction

Since the classical work of Prehn and Main [1] demonstrating that vaccination against chemically induced murine tumors was feasible, there were numerous attempts to treat human tumors using immunological strategies Most of the former trials were disappointing, a deeper understanding of the cellular and molecular aspects of the immune response (IR), achieved in the last 20 years, prompted the development of new schedules of immunotherapy against cancer, including vaccines combined with anti-Treg or anti-myeloid-derived suppressor cells antibodies and, more recently, immune-checkpoint inhibitors, such as antibodies against cytotoxic T lymphocyte-antigen 4 (CTLA-4) or against programmed death-ligand 1 (PD-L1) [2,3,4,5,6]. The biphasic nature of the IR curve on which the so-called immunostimulatory theory of cancer was based, entails the ambiguous suggestion that immunological strategies might be good therapeutic options against cancer and might run a real risk of doing harm if the immunity induced by them is too weak to move the reaction beyond the tumorstimulatory part of the IR curve [8, 10].

Methods

Results

Conclusion