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.

中文翻译：

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抑制骨髓细胞中的雌激素信号传导可增加黑色素瘤的肿瘤免疫力

免疫检查点阻断 (ICB) 疗法显着延长了多种肿瘤类型的患者生存期，尤其是在黑色素瘤中。有趣的是，已经观察到对 ICB 反应的性别特异性差异，男性从 ICB 中获得的益处大于女性，尽管这种差异背后的机制或机制尚不清楚。挖掘已发表的转录组数据集，我们确定对 ICB 的反应受肿瘤内巨噬细胞功能的影响。这将我们的观察结果纳入背景，即雌激素 (E2) 通过雌激素受体α (ERα ) 通过使巨噬细胞极化偏向促进 CD8 ⁺的免疫抑制状态来刺激小鼠模型中的黑色素瘤生长。T细胞功能障碍和衰竭以及ICB抵抗。这种活性在巨噬细胞特异性缺失 ER α的小鼠中并不明显，这证实了骨髓细胞内雌激素信号传导在建立免疫抑制状态中的直接作用。使用选择性雌激素受体下调剂 (SERD) 氟维司群抑制 ER α ，可减少肿瘤生长，刺激适应性免疫，并提高 ICB 的抗肿瘤功效。此外，决定巨噬细胞中 ER 活性的基因特征预测了接受 ICB 治疗的黑色素瘤患者的存活率。这些结果突出了 E2/ER 信号作为肿瘤内巨噬细胞极化调节剂的重要性，这种活性可以在治疗上靶向逆转免疫抑制并提高 ICB 功效。