Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Interleukin-1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. Here, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAMs) to inhibit BTIC self-renewal and CD8+ T cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1β increased PD-L1 expression by interacting with the transcription factor yin yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PD-L1. Combined treatment with an IL1R2-neutralizing antibody and anti-PD-1 led to enhanced anti-tumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes.

中文翻译：

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IL1R2 阻断可减轻三阴性乳腺癌的免疫抑制并增强抗 PD-1 功效


三阴性乳腺癌 (TNBC) 是一种侵袭性乳腺癌亚型，治疗选择有限。 2 型白细胞介素 1 受体 (IL1R2) 促进 TNBC 中乳腺肿瘤起始细胞 (BTIC) 的自我更新和肿瘤生长，表明靶向它可以改善患者的治疗。在这里，我们观察到 IL1R2 阻断强烈减弱巨噬细胞的募集和肿瘤相关巨噬细胞 (TAM) 的极化，从而抑制 BTIC 自我更新和 CD8+ T 细胞耗竭，从而减少 TNBC 小鼠模型的肿瘤负荷并延长生存期。 TAM 衍生的 IL1β 激活 IL1R2，通过与 TAM 和 TNBC 细胞中转录因子 yin yang 1 (YY1) 相互作用并诱导 YY1 泛素化和蛋白酶体降解来增加 PD-L1 表达。 YY1 的缺失减轻了 c-Fos 的转录抑制，c-Fos 是 PD-L1 的转录激活剂。 IL1R2 中和抗体和抗 PD-1 联合治疗可增强抗肿瘤功效，并减少 TAM、BTIC 和耗尽的 CD8+ T 细胞。这些结果表明，IL1R2 阻断可能是增强 TNBC 免疫检查点阻断功效以改善患者预后的策略。