Optimizing the efficacy of dual-costimulation cancer therapy by engaging tumor-unrelated CD4 T cell help (TUM2P.1009)

Tumor escape following immune therapy can be caused by loss of specifically targeted MHC class I-restricted epitopes. It would thus be beneficial to develop therapies that engage multipronged anti-tumor responses. Agonist mAbs to the TNF/TNFR family costimulatory receptors CD134 plus CD137 (dual costimulation) not only elicits CD8 + CTL, but also cytotoxic CD4 Th1 cells that can directly target MHC-II + tumors. Further, dual costimulated cytotoxic CD4 Th1 cells not only provide linked help to CD8 T cells responding to cross-presented antigen, but can also provide non-linked help that programs Th1/Tc1 functions in antigen-non-responding (bystander) T cells. Here we tested whether engagement of tumor-unrelated CD4 help augments dual costimulation-mediated control of established B16 melanoma that can be induced to express both MHC class I and II. Notably, engagement of tumor-unrelated CD4 T cells dramatically enhanced the ability of dual costimulation to control B16 tumor growth, this effect depended upon both CD8 and CD4 cells, and therapeutic efficacy correlated with increased tumor infiltration of GzmB-expressing effector CD8 and CD4 T cells with a concomitant decrease in Foxp3 + CD4 + cells. Interestingly, the dual costimulated tumor-unrelated CD4 helper T cells themselves appear to require help from a CD134-responsive but presumably antigen-non-responding cell to attain their maximal function.