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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 Article has an altmetric score of 36

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

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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 6

Pharmacological depletion of the ER reverses E2-dependent melanoma tumor growth.

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Pharmacological depletion of the ER reverses E2-dependent melanoma tumor...
(A–C) Growth of B16F10 (0.5 × 105) (n = 9), YuMM5.2 (5 × 105) (n = 6), and BPD6 (5 × 105) (n = 5) tumors in ovariectomized C57BL/6J mice supplemented with placebo or E2 and cotreated with the ERα antagonist fulvestrant (ful). (D) Quantification of the ratio of M1/M2 macrophages isolated from BPD6 tumors in B. (E–G) Quantification of M1 macrophages (MHCIIhiCD206–), CD8+GZMB+ T cells and CD8+PD-1+ T cells in YuMM5.2 tumors from C (n = 4). (H) Individual volumes of BPD6 tumors implanted into ovariectomized mice treated with placebo or E2 following cotreatment with fulvestrant and ICB (α–PD-1 plus α-CTLA4), either alone or in combination. Vehicle plus IgG (E2 + Veh; n = 10; red); fulvestrant plus IgG (E2 + ful + ICB; n = 15; blue); vehicle plus ICB (E2 + ICB; n = 15; black); and fulvestrant plus ICB (E2 + ful; n = 15; brown). Black arrow indicates the start of the ICB treatment regimen. (I) Tumor volumes of BPD6 measured at day 12 after inoculation. (J) Individual volumes of B16F10 tumors implanted into ovariectomized C57BL6/J mice supplemented with placebo or E2 and cotreated with fulvestrant along with ICB (α–PD-1). Vehicle plus IgG (n = 9, red); fulvestrant plus IgG (n = 8, blue); vehicle plus ICB (n = 9, black); and fulvestrant plus ICB (n = 10 brown). Black arrow indicates the start of the α–PD-1 treatment regimen. (K and L) B16F10 tumor volumes measured on day 16 (all 4 groups) and day 22 (E2 plus fulvestrant vs. E2 plus fulvestrant plus α–PD-1 groups) after inoculation. (M) Median overall survival of all patients treated with immunotherapy (pembrolizumab or nivolumab alone, or in combination with ipilimumab) from the Gide et al. data set (32), with high or low E2-downregulated gene signatures derived from CD68+ cells in the scRNA-Seq experiments. Data in A– C are representative of 2 individual experiments. Data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA (A–C), 1-way ANOVA followed by Bonferroni’s multiple-correction test (E–G, I, and K), Student’s t test (D and L), and log-rank test (M).

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