BET INHIBITION BOOSTS THE IMMUNOGENICITY ENHANCING EFFECTS OF VIRAL RNA MIMICS AND INCREASES T-CELL RECOGNITION IN MELANOMA

The success of immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) has been noteworthy. However, many immunotherapies fail to produce clinical benefits in large patient groups, highlighting the need for novel approaches to improve cancer immunotherapy efficacy. One primary reason for ineffective responses to immunotherapy is low tumor immunogenicity, caused by dysregulated interferon (IFN) signaling or pathways governing the presentation of tumor antigens through human leukocyte antigen (HLA) class I. Promising pathways to overcome therapy resistance in cancer involve the activation of antiviral signaling pathways mediated by retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) cytosolic receptors. Activation of these antiviral pathways has been associated with improved immunotherapy response and potentially serves as an alternative to IFN signaling resistance. In this study, we investigated the impact of inhibiting the bromodomain and extra-terminal domain (BET) protein family on sensitizing antiviral signaling pathways in melanoma. Treatment of melanoma cell lines with the BET inhibitor JQ1 resulted in the upregulation of key proteins within the RIG-I/MDA5 antiviral signaling pathway, notably the MAVS protein. Moreover, we developed an optimized sequential treatment regimen using JQ1 and Poly(I:C), a synthetic double-stranded RNA viral mimic. This regimen enhanced the antiviral response within the tumor cells, leading to increased expression of HLA class I proteins on the tumor cells and improved recognition by autologous tumor-infiltrating lymphocytes (TIL). To the best of our knowledge, this study is the first to suggest that BET inhibitors, in combination with a dsRNA mimic, could enhance the efficacy of cancer immunotherapy.