Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion

CD47 on tumor cells protects from phagocytosis, while PD-L1 dampens T cell-mediated tumor killing. However, whether and how CD47 and PD-L1 coordinate is poorly understood. We reveal that CD47 and PD-L1 on tumor cells coordinately suppress innate and adaptive sensing to evade immune control. Targeted blockade of both CD47 and PD-L1 on tumor cells with a bispecific anti-PD-L1-SIRPα showed significantly enhanced tumor targeting and therapeutic efficacy versus monotherapy. Mechanistically, systemic delivery of the dual-targeting heterodimer significantly increased DNA sensing, DC cross-presentation, and anti-tumor T cell response. In addition, chemotherapy that increases “eat me” signaling further synergizes with the bispecific reagent for better tumor control. Our data indicate that tumor cells evolve to utilize both innate and adaptive checkpoints to evade anti-tumor immune responses and that tumor cell-specific dual-targeting of both checkpoints represents an improved strategy for tumor immunotherapy. CD47 and PD-L1 serve as critical innate and adaptive checkpoints, respectively. Liu et al. show CD47 and PD-L1 coordinate in tumor cells to evade immune response. Furthermore, a bispecific antibody design enables better targeting on tumor cells, but less on non-tumor cells, and enhanced therapeutic efficacy.