CD317-mediated cell cytoskeleton regulation as a novel means of tumor immune evasion

Abstract

Abstract CD317 is frequently overexpressed in various human cancers. Although our previous study had demonstrated its pro-proliferative role in HCC development, the functions of CD317 in tumorigenesis, especially in tumor immune evasion, remain unclear. Herein we report that CD317 protects cancer cells from immune cell-mediated cytotoxicity. CD317 knockdown in cancer cells affects neither cell-cell conjugation nor effector cell activation, but markedly increases the vulnerability of cancer cells by which renders cancer cells more sensitive to YTS- or CAR-modified NK cell-mediated cytotoxicity. This sensitivity alteration cannot be restored by adding recombinant CD317 extracellular domain (317ECD) protein, excluding the possibility that CD317 acts as a traditional immune checkpoint protein that provides inhibitory signaling to effector cells. Mechanically, immunoprotective function of CD317 is mainly dependent on the interaction with RICH2, a known CD317-binding partner that is involved in the cytoskeleton regulation. Knocking down RICH2 significantly rendered CD317 incapable of protecting cancer cells from immune cell-mediated killing, suggesting CD317 facilitates tumor immune evasion by regulating tumor cell cytoskeleton to confront immune killing. Taken together, our findings reveal a novel means of tumor immune evasion and suggest CD317 as an attractive target for improving the efficiency of cancer immunotherapy.