Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

eLife

Ben Z Stanger¹  Jinyang Li¹  Ankit Dahal²  Junqian Zhang²  Tzvete Dentchev²  Christopher A Natale²  Todd W Ridky² 

[1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States;Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia, United States;

关键词: GPER;    GPCR;    melanoma;   

DOI  :  10.7554/eLife.31770

来源: DOAJ

【 摘 要 】

Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.

【 授权许可】

Unknown