Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Journal Article (Journal Article)

Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.

Full Text

Duke Authors

Cited Authors

  • Chakraborty, B; Byemerwa, J; Shepherd, J; Haines, CN; Baldi, R; Gong, W; Liu, W; Mukherjee, D; Artham, S; Lim, F; Bae, Y; Brueckner, O; Tavares, K; Wardell, SE; Hanks, BA; Perou, CM; Chang, C-Y; McDonnell, DP

Published Date

  • December 1, 2021

Published In

Volume / Issue

  • 131 / 23

PubMed ID

  • 34637400

Pubmed Central ID

  • PMC8631601

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI151347

Language

  • eng

Conference Location

  • United States