Combinatorial Immunotherapies Overcome MYC-Driven Immune Evasion

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission 1 . Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response 1-5 . Whether specific oncogenes diminish response to immunotherapy 6-10 and whether these effects are reversible remains poorly understood. We predicted that MYC , an oncogene that is frequently overexpressed 11,12 and is associated with worse prognosis 12 , may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.