Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma
Binita Chakraborty, … , Ching-Yi Chang, Donald P. McDonnell
Binita Chakraborty, … , Ching-Yi Chang, Donald P. McDonnell
Published October 12, 2021
Citation Information: J Clin Invest. 2021;131(23):e151347. https://doi.org/10.1172/JCI151347.
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Research Article Oncology

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

Abstract

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.

Authors

Binita Chakraborty, Jovita Byemerwa, Jonathan Shepherd, Corinne N. Haines, Robert Baldi, Weida Gong, Wen Liu, Debarati Mukherjee, Sandeep Artham, Felicia Lim, Yeeun Bae, Olivia Brueckner, Kendall Tavares, Suzanne E. Wardell, Brent A. Hanks, Charles M. Perou, Ching-Yi Chang, Donald P. McDonnell

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Figure 1

A decreased M1/M2 ratio compromises the immunotherapy benefit for patients with melanoma.

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A decreased M1/M2 ratio compromises the immunotherapy benefit for patien...
(A and B) Relative proportion of M1 macrophages as determined by CIBERSORT or the ratio of M1/M2 macrophages in patients with melanoma, parsed by their response to immunotherapy in the same patient cohort. BH, Benjamini-Hochberg; Ipi, ipilimumab; Nivo, nivolumab; Pembro, pembrolizumab; RECIST, Response Evaluation Criteria in Solid Tumors. (C and D) Median overall survival for all patient cohorts (32) treated with immunotherapy with either high or low proportions of M1 macrophages or M1/M2 ratios as determined by CIBERSORT. (E) Median overall survival for all patient cohorts treated with ipilimumab alone (33) or either pembrolizumab or nivolumab alone (34), with either high or low M1/M2 signature ratios as determined by CIBERSORT. (F and G) CD68, CSF1, CSF1R, and PDCD1 expression in patients with melanoma who were classified as nonresponders (n = 13) or responders (n = 12) to α–PD-1 therapy, obtained from data sets from Hugo et al. (34). Both responders and nonresponders were stratified according to CYP19A1hi and CYP19A1lo median expression. Significance was calculated using a paired Student’s t test (A and B), an unpaired Student’s t test (F and G), and a log-rank test (C–E).