PKC ? Germline Variants and Genetic Deletion in Mice Augment Anti-Tumor Immunity Through Regulation of Myeloid Cells

Antibodies blocking the PD-1/PD-L1 axis and other immune checkpoints have revolutionized cancer care. Clinical response is favored in tumors showing a T cell-inflamed tumor microenvironment at baseline 1,2, which is tremendously variable between patients and also across tumor types 3. Despite the importance of this immunobiological phenotype, the mechanisms explaining such inter-patient heterogeneity are just beginning to be understood. Based on the notion that hypomorphic germline variants in immunoregulatory genes are linked to autoimmune diseases 4, one hypothesis is that germline variants might favor spontaneous immune priming and T cell infiltration into tumors. To investigate this possibility, we utilized TCGA data and identified germline variants in the PKC gene associated with decreased expression of PRKCD and an increased immune gene signature in the tumor microenvironment. Genetic deletion of PKC in mice resulted in improved endogenous anti-tumor immunity and increased efficacy of PD-1/PD-L1 blockade. Single cell RNAseq of immune cells in the tumor revealed expression of Prkcd in myeloid cells, and PKC deletion caused a macrophage shift from an M2-like to an M1-like phenotype. Conditional deletion of PKC in macrophages recapitulated the improved tumor control phenotype and response to anti-PD-L1 treatment. Analysis of clinical samples from melanoma patients confirmed an association between PRKCD variants and M1/M2 phenotype, and between a PKC KO-like gene signature and clinical benefit from anti-PD-1. Our results suggest that reduced PKC in host cells leads to improved anti-tumor immunity and PD-1 blockade efficacy through a myeloid shift to an M1-like phenotype, and further identify PKC as a candidate therapeutic target.