Title: BET Inhibition Triggers Anti-tumor Immunity by Enhancing MHC Class I Expression in Head and Neck Squamous Cell Carcinoma.

BET inhibition has been shown to have a promising anti-tumor effect in multiple tumors. However, the impact of BET inhibition on anti-tumor immunity was still not well documented in HNSCC. In this study, we aim to assess the functional role of BET inhibition in anti-tumor immunity and clarify its mechanism. We show that BRD4 is highly expressed in HNSCC and inversely correlated with the infiltration of CD8 T cells. BET inhibition potentiates CD8 T-cell based anti-tumor immunity in vitro and in vivo. Mechanistically, BRD4 acts as a transcriptional suppressor and represses the expression of MHC class I molecules by recruiting G9a. Pharmacological inhibition or genetic depletion of BRD4 potently increases the expression of MHC class I molecules in the absence and presence of IFN-γ. Moreover, compared to PD-1 blocking antibody treatment or JQ1 treatment individually, the combination of BET inhibition with anti-PD-1 antibody treatment significantly enhances the anti-tumor response in HNSCC. Taken together, our data unveils a novel mechanism by which BET inhibition potentiates anti-tumor immunity via promoting the expression of MHC class I molecules and provides a rationale for combination of ICBs with BET inhibitors for HNSCC treatment.