三阴性乳腺癌
封锁
癌症研究
CD8型
医学
乳腺癌
免疫学
癌症
免疫系统
受体
内科学
作者
Jie Xia,Lixing Zhang,Xiaojin Peng,Juchuanli Tu,Siqin Li,Xingzhi He,Fengkai Li,Jiankun Qiang,Haonan Dong,Qiaodan Deng,Cuicui Liu,Jiahui Xu,R R Zhang,Quentin Liu,Guohong Hu,Chong Liu,Yi‐Zhou Jiang,Zhi‐Ming Shao,Ceshi Chen,Suling Liu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-04-24
标识
DOI:10.1158/0008-5472.can-23-3429
摘要
Abstract 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.
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