文章 : 

分泌IL-17A的γδ T细胞通过CX3CR1+巨噬细胞促进HR+HER2−乳腺癌对CDK4/CDK6抑制剂的耐药性

IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HR+HER2− breast cancer via CX3CR1+ macrophages

原文发布日期：2019-11-18 

英文摘要：

Resistance to cyclin-dependent kinase 4/6 (CDK4/CDK6) inhibitors leads to treatment failure and disease progression in women with hormone receptor+HER2− (HR+HER2−) breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting interleukin-17A (IL-17A)-secreting γδ T cells to mouse HR+HER2− BCs following CDK4/CDK6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL-17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of individuals with HR+HER2− BC. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of individuals with HR+HER2− BC receiving CDK4/CDK6 inhibitors. Intratumoral γδ T cells were increased in post- versus pretreatment biopsies from individuals with HR+HER2− BC relapsing on CDK4/CDK6 inhibitors. CX3CR1+ TAMs had negative prognostic impact in women with HR+HER2− BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, γδ T cells and CX3XR1+ TAMs may favor resistance to CDK4/CDK6 inhibitors in individuals with HR+HER2− BC.

摘要翻译：

对细胞周期蛋白依赖性激酶4/6（CDK4/CDK6）抑制剂的耐药性会导致激素受体阳性HER2阴性（HR+HER2−）乳腺癌（BC）患者治疗失败及疾病进展。我们揭示了一种低氧敏感、CCL2依赖性通路：在小鼠HR+HER2−乳腺癌模型中，CDK4/CDK6抑制后，该通路会招募分泌白细胞介素-17A（IL-17A）的γδ T细胞，导致肿瘤相关巨噬细胞（TAMs）向与耐药性相关的免疫抑制性CX3CR1+表型重极化。在两项HR+HER2−乳腺癌患者队列中，IL-17A信号增强和瘤内γδ T细胞丰度与肿瘤高级别和/或生存期缩短呈正相关。另一组接受CDK4/CDK6抑制剂治疗的HR+HER2−乳腺癌患者中，循环γδ T细胞和血浆CCL2水平与疾病进展呈负相关。对CDK4/CDK6抑制剂耐药复发的HR+HER2−乳腺癌患者，其治疗后活检组织中瘤内γδ T细胞较治疗前显著增加。在接受新辅助PD-1阻断联合放疗的HR+HER2−乳腺癌女性患者中，CX3CR1+ TAMs具有负面预后影响。因此，γδ T细胞与CX3XR1+ TAMs可能促进HR+HER2−乳腺癌患者对CDK4/CDK6抑制剂产生耐药性。

原文链接：

 https://www.nature.com/articles/s43018-025-01007-z