JAK2 inhibition prevents NK-released IFNγ-mediated PD-L1 upregulation and enhances cetuximab mediated ADCC of HNC cells (TUM2P.1014)

Abstract

Abstract Programmed death ligand 1 (PD-L1) is an immunosuppressive molecule expressed by many cancer types, including a large proportion of head and neck cancers (HNC), and ligation of its receptor, programmed death 1 (PD-1), induces exhaustion of effector T cells, however its expression level and function on natural killer (NK) cells is not well characterized yet. It has been shown that interferon gamma (IFNγ) induces PD-L1 expression in many cancer types including glioblastoma, melanoma, lung and head and neck cancer (HNC). IFNγ signals through Janus Kinase 1/2 (JAK1/2) heterodimer complex and mediates signal transducer and activator of transcription 1 (STAT1) phosphorylation. Herein we demonstrate that IFNγ-mediated tumor cell PD-L1 expression is JAK2/STAT1 but not JAK1 dependent. Interestingly, NK cell activation through CD16 ligation of cetuximab coated tumor targets increased IFNγ release and PD-1 expression on NK cells. Therefore, blocking PD-L1/PD-1 axis is crucial in order to increase NK mediated antibody dependent cell cytotoxicity (ADCC). Herein, we demonstrate that specific JAK2 inhibition downregulated NK cell-derived IFNγ induced PD-L1 expression in tumor targets and enhanced cetuximab mediated ADCC. Our data suggest a crucial role for JAK2 in IFNγ mediated tumor cell PD-L1 upregulation. Importantly, JAK2 inhibition provides a logical strategy to increase tumor cell lysis through suppressing tumor cell PD-L1 expression in combination with anti-EGFR cetuximab therapy.