PT  - JOURNAL ARTICLE
AU  - Christopher A. Natale
AU  - Jinyang Li
AU  - Junqian Zhang
AU  - Ankit Dahal
AU  - Ben Z. Stanger
AU  - Todd W. Ridky
TI  - Non-classical estrogen signaling inhibits melanoma and improves response to PD-1 blockade
AID  - 10.1101/146498
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 146498
4099  - http://biorxiv.org/content/early/2017/06/06/146498.short
4100  - http://biorxiv.org/content/early/2017/06/06/146498.full
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.