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

Christopher A Natale | Jinyang Li | Junqian Zhang | Ankit Dahal | Tzvete Dentchev | Ben Z Stanger | Todd W Ridky
eLife | 2018

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.

Pubmed ID: 29336307

Associated grants

  • Agency: NIAMS NIH HHS, United States
    Id: P30 AR069589
  • Agency: NCI NIH HHS, United States
    Id: F31 CA206325
  • Agency: NCI NIH HHS, United States
    Id: P50 CA174523
  • Agency: NIAMS NIH HHS, United States
    Id: T32 AR007465
  • Agency: NCI NIH HHS, United States
    Id: R01 CA163566

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