RT Journal Article
SR Electronic
T1 Non-classical estrogen signaling inhibits melanoma and improves response to PD-1 blockade
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 146498
DO 10.1101/146498
A1 Christopher A. Natale
A1 Jinyang Li
A1 Junqian Zhang
A1 Ankit Dahal
A1 Ben Z. Stanger
A1 Todd W. Ridky
YR 2017
UL http://biorxiv.org/content/early/2017/06/06/146498.abstract
AB Female sex and pregnancy are associated with reduced risk of melanoma and improved stage specific survival; however, the mechanism underlying this apparent clinical benefit is unknown. We previously discovered that pregnancy-associated 17β-estradiol drives melanocyte differentiation by activating the nonclassical G-protein coupled estrogen receptor (GPER). Here, we show that pregnancy inhibits melanoma, and that transient GPER activation induces long-term changes in melanocytes, which are associated with increased cellular differentiation and resistance to melanoma. A selective GPER agonist induced c-Myc protein degradation, slowed tumor growth, and inhibited expression of immune suppressive proteins including PD-L1, suggesting that GPER signaling may render melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated synergistically with PD-1 blockade in melanoma-bearing mice to dramatically extend survival. These results thus define GPER as a target for differentiation-based melanoma therapy.Significance Immune checkpoint inhibitors including αPD-1 induce durable remissions in only 30% of patients with advanced melanoma. This work demonstrates that αPD-1 efficacy is significantly improved by systemic delivery of a selective agonist of the nonclassical estrogen receptor, GPER, which drives melanoma differentiation and renders tumors more vulnerable to the immune system.