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.