Rationalized combinatorial targeting of immune co-receptors leads to tumor regression.

Different co-stimulatory and co-inhibitory molecules influence the dynamicity of an immune response. As their expression levels may collectively decide the amplitude and quality of an anti-tumor immune response, we proposed that the expression of these molecules would be dynamically modulated during a progressive tumor growth and that the study of their expression levels would guide fixing a combinatorial target for anti-tumor immunotherapy. Based on the kinetics of expression of 33 immune molecules within the tumor and draining lymph nodes during RM-1-induced progressive prostate tumor model in C57BL/6 mice, a three-phase combinatorial anti-tumor immunotherapy was designed. Phase- specific treatments with combinations of blocking antibodies against co-inhibitory receptors and agonistic antibodies against stimulatory receptors resulted in significant tumor regression and cytokines' expression, suggesting a strategic personalized anti-tumor immunotherapy with enhanced therapeutic efficacy, reduced toxicity and the risk of treatment failures.