An immunological mechanism of resistance to CDK4/6 inhibitors in breast cancer

We harnessed an immunocompetent model of HR+HER2- breast cancer with unique translational features4 to mechanistically delineate a novel CCL2-depedent pathway leading to the recruitment of IL17A-secreting gamma-delta T cells to the tumor microenvironment after CDK4/6 inhibition, culminating with the repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive, CX3CR1+ phenotype. Such a mechanism could be averted by focal radiotherapy, reflecting the inability of hypoxic tumor areas (which are initially enriched by radiotherapy owing to their intrinsic radio-resistance) to secrete CCL2 in response to CDK4/6 inhibitors. Our findings suggest that gamma-delta T cells and CX3CR1+ TAMs may favor clinical resistance to CDK4/6 inhibitors in some patients with HR+HER2- breast cancer.本研究采用具备独特转化特征的免疫健全激素受体阳性、人表皮生长因子受体2阴性（HR+HER2-）乳腺癌模型[4]，从机制层面阐明了一条全新的CCL2（CC chemokine ligand 2）依赖性通路：在接受CDK4/6抑制剂治疗后，该通路可介导分泌IL17A（interleukin 17A）的γδ T细胞（gamma-delta T cells）向肿瘤微环境募集，最终促使肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）复极化为免疫抑制性CX3CR1+表型。局部放疗可阻断这一机制——缺氧肿瘤区域因自身固有放射抵抗性，初始放疗会使其富集，而此类区域无法在CDK4/6抑制剂刺激下分泌CCL2。本研究结果提示，在部分激素受体阳性、人表皮生长因子受体2阴性（HR+HER2-）乳腺癌患者中，γδ T细胞与CX3CR1+ TAMs可能会促进其对CDK4/6抑制剂的临床耐药。