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

Abstract

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.

BRDT is a novel regulator of eIF4EBP1 in renal cell carcinoma

“…BRDT inhibitors, including PLX51107 and INCB054329, have been demonstrated to suppress the progression of lung cancer cells, bladder cancer cells and intestinal cancer cells ( 24 , 25 ). The present study first analyzed the function of PLX51107 and INCB054329 on various RCC cell lines.…”

PLX3397 inhibits the accumulation of intra‐tumoral macrophages and improves bromodomain and extra‐terminal inhibitor efficacy in melanoma

“…Time course studies established that PLX51107 was present at ~1–2 µg/ml, and PLX3397 was present at ~20–60 µg/ml in the blood plasma of treated mice (Figure A). PLX51107 significantly increased CD8+ T cells in D4M3.A tumors during treatment, as previously demonstrated (Erkes et al, ), but did not alter the influx of CD8+ T cells in YUMM1.7 tumors (Figure B). We previously showed that expression of PD‐L1, a therapeutic target of BETi (Zhu et al, ), was decreased by PLX51107 treatment in D4M3.A tumors (Erkes et al, ), suggesting that BET inhibition is achieved in vivo .…”

“…To analyze tumor‐infiltrating lymphocytes by flow cytometry, tumors were dissected and processed into single‐cell suspensions. Cells were stained with a fixable live/dead stain followed by surface antibody staining, as previously described (Erkes et al, ). Cells were surface stained with the following antibodies clones from Biolegend: CD45.2 (104), CD11c (N418), CD11b (M1/70), CD103 (2E7), F4/80 (BM8), CD3 (17A2), CD19 (6D5), CD206 (C068C2) I‐A/I‐E (M5/114.15.1), CD8α (53–6.7), and CSF‐1R (AFS98).…”

“…After intradermal cell implantation, tumors were grown to ~50 mm 3 , and then, mice were fed either control or PLX51107‐laced chow. D4M3.A tumors displayed robust tumor growth delay with PLX51107 treatment, as previously described (Erkes et al, ) in contrast, YUMM1.7 tumors exhibited only modest growth delay (Figure a). Accordingly, PLX51107 prolonged animal survival by ~20 days, and only ~5 days in mice bearing D4M3.A and YUMM1.7 tumors, respectively (Figure b).…”

“…We note that PLX3397 inhibits other tyrosine kinases besides CSF‐1R, such as cKIT, FLT3, and PDGFR‐ß, that may also contribute to the regulation of melanoma growth (Cannarile et al, ). PLX51107 can inhibit cancer cell growth in vitro; however, in vivo we observe additional effects on the tumor immune microenvironment (Erkes et al, ). Further investigation is required to thoroughly understand the effects of PLX51107 on diverse immune cell types within the tumor.…”