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Accepted (AM)Open Access (License Unspecified), Open
Journal article
The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner
Pigment cell and melanoma research, v 32(5), pp 687-696
01 Sep 2019
PMID: 31063649
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 micro-environment. 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.
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Details
- Title
- The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner
- Creators
- Dan A. Erkes - Thomas Jefferson UniversityConroy O. Field - Thomas Jefferson UniversityClaudia Capparelli - Thomas Jefferson UniversityManoela Tiago - Thomas Jefferson UniversityTimothy J. Purwin - Thomas Jefferson UniversityInna Chervoneva - Thomas Jefferson UniversityAdam C. Berger - Thomas Jefferson UniversityEdward J. Hartsough - Drexel UniversityJessie Villanueva - The Wistar InstituteAndrew E. Aplin - Thomas Jefferson University
- Publication Details
- Pigment cell and melanoma research, v 32(5), pp 687-696
- Publisher
- Wiley
- Number of pages
- 10
- Grant note
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation CA056036; CA16672 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) K99CA207855 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA160495; CA196278; CA207855; CA114046 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA PF-18-096-01-LIB / American Cancer Society
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000481578200007
- Scopus ID
- 2-s2.0-85066101708
- Other Identifier
- 991019168461204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology
- Dermatology
- Oncology