The next‐generation BET inhibitor, PLX51107, delays melanoma growth in a CD8‐mediated manner

• Published in: Pigment cell and melanoma research Vol. 32; no. 5; pp. 687 - 696
• Main Authors: Erkes, Dan A., Field, Conroy O., Capparelli, Claudia, Tiago, Manoela, Purwin, Timothy J., Chervoneva, Inna, Berger, Adam C., Hartsough, Edward J., Villanueva, Jessie, Aplin, Andrew E.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2019
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; anti‐PD‐1 non‐responsive; Apoptosis; BET inhibitor; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Cox2; Cyclooxygenase-2; Dendritic cells; FasL protein; Humans; Immune system; Immunity; Lymphocytes; Lymphocytes T; Male; Melanoma; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Metastases; Mice; Mice, Inbred C57BL; Oxazoles - pharmacology; Oxazoles - therapeutic use; PD-L1 protein; Proteins - antagonists & inhibitors; Pyridines - pharmacology; Pyridines - therapeutic use; Pyrroles - pharmacology; Pyrroles - therapeutic use; T cells; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; melanoma; BET inhibitor; anti-PD-1 non-responsive; T cells; Cox2
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12788

Epigenetic agents such as bromodomain and extra‐terminal region inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next‐generation BETi that are potent and display a favorable half‐life. Here, we tested the BETi, PLX51107, for immune‐based effects on tumor growth in BRAF V600E melanoma syngeneic models. PLX51107 delayed melanoma tumor growth and increased activated, proliferating, and functional CD8+ T cells in tumors leading to CD8+ T‐cell‐mediated tumor growth delay. PLX51107 decreased Cox2 expression, increased dendritic cells, and lowered PD‐L1, FasL, and IDO‐1 expression in the tumor microenvironment. Importantly, PLX51107 delayed the growth of tumors that progressed on anti‐PD‐1 therapy; a response associated with decreased Cox2 levels, decreased PD‐L1 expression on non‐immune cells, and increased intratumoral CD8+ T cells. Thus, next‐generation BETi represent a potential first‐line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on antitumor CD8+ T cells.