CD47 on tumors inhibits phagocytosis, while PD-L1 limits T cell-mediated tumor killing. However, whether and how these two pathways coordinately evade immune responses are poorly understood. We reveal that both CD47 and PD-L1 on tumors coordinately evade innate and adaptive sensing. Targeted blockade of CD47 and PD-L1 on tumor cells with bispecific anti-PDL1-SIRPα showed better therapeutic efficacy than single blockades with reduced off-tumor targeting. Mechanistically, the dual-targeting approach significantly enhanced DNA sensing in dendritic cells (DC), DC cross-presentation and anti-tumor T cell response. Our data indicate that tumor cells evolve to utilize two-levels of checkpoints to evade anti-tumor immune responses, and tumor cell-specific dual-targeting of both innate and adaptive checkpoints represents a new strategy for increasing efficacy and reducing toxicity.

Citation Format: Yang-Xin Fu, Xiaojuan Liu. Dual targeting of innate and adaptive checkpoints on tumor cells limits immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4557.