Therapeutic targeting of the p300/CBP bromodomain enhances the efficacy of immune checkpoint blockade therapy.

Blockade of immune checkpoints, such as programmed death-ligand 1 (PD-L1), has shown promise in cancer treatment; however, clinical response remains limited in many cancer types. Our previous research demonstrated that p300/CBP mediates the acetylation of the PD-L1 promoter, regulating PD-L1 expression. In this study, we further investigated the role of the p300/CBP bromodomain in regulating PD-L1 expression using CCS1477, a selective bromodomain inhibitor developed by our team. We found that the p300/CBP bromodomain is essential for H3K27 acetylation at PD-L1 enhancers. Inhibiting this modification significantly reduced enhancer activity and PD-L1 transcription, including exosomal PD-L1, which has been implicated as key contributors to resistance against PD-L1 blockade therapy in various cancers. Furthermore, CCS1477 treatment resulted in a marked reduction of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) by inhibiting key cytokines such as IL6, CSF1, and CSF2, which are crucial for MDSC differentiation and recruitment. By reducing PD-L1 expression and modulating the immunosuppressive TME, CCS1477 creates a more favorable environment for tumor-infiltrating lymphocytes, significantly enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Notably, these effects were observed in both prostate cancer and melanoma models, underscoring the broad therapeutic potential of p300/CBP bromodomain inhibition in improving ICB outcomes.