Abstract
Most patients with breast cancer (BC) and soft tissue sarcoma (STS) harbor immunologically cold tumors and do not respond to existing immunotherapies such as immune checkpoint inhibitors (ICIs) as a monotherapy. Consequently, prolonged treatment with highly toxic multiagent chemotherapy, with or without ICIs, remains the mainstay of systemic therapy in such patients. Therefore, there is an acute clinical need for novel chemotherapy-free immunotherapy regimens with high efficacy and minimal toxicity. Here, employing an in vivo drug screen, we identify that a short course of radiation therapy (RT) synergizes with pharmacological bromodomain and extraterminal (BET) inhibition to elicit a strong systemic anti-tumor immunity and long-term immunological memory in a CD8+ T cell-dependent manner in murine models of both BC and STS. Mechanistic studies reveal that RT + BET inhibition accentuates RT-induced DNA damage and micronuclei formation, increases Major Histocompatibility Complex class I and II expression on macrophages, enhances translocation of calreticulin to the plasma membrane, and blocks RT-induced Programmed Death-Ligand 1 (PD-L1) overexpression on tumor cells, thereby promoting immunogenic cell death. Our data suggest that a combination of RT + BET inhibition promotes robust anti-tumor immunity and immunological memory in immunologically cold tumors, thereby opening potential avenues for clinical translation.