Radiation synergizes with BET inhibition to stimulate durable, systemic anti-tumor immunity in murine cancer models

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 <i>in vivo</i> 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.