Principal Investigator – Weill Cornell Medical College
While CDK4/6 inhibitors have been successfully implemented into the clinical management of advanced/metastatic HR+HER2- breast cancer, the majority of these patients ultimately progress and succumb to their disease, calling for the identification of clinically actionable resistance mechanisms.
Here, we harnessed an immunocompetent model of HR+HER2- breast cancer with unique translational features to mechanistically delineate a novel radiotherapy-preventable, CCL2-depedent pathway leading to the recruitment of hypoxia-sensitive, IL17A-secreting γδ T cells to the tumor microenvironment upon CDK4/6 inhibition, culminating with the repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive, CX3CR1+ phenotype. Consistent with mouse data, genetic signatures of IL17A signaling or γδ T cell infiltration, as well as the intratumoral levels of γδ T cells or CX3CR1+ TAMs, were associated with reduced disease specific survival or advanced tumor grade in two independent cohorts of patients with HR+HER2- breast cancer.
Similarly, high levels of circulating γδ T cells at baseline were negatively linked to progression-free survival in two series of patients with HR+HER2- breast cancer receiving CDK4/6 inhibitors, as were plasma CCL2 levels. Moreover, intratumoral γδ T cells were increased in biopsies from patients with HR+HER2- breast cancer relapsing on CDK4/6 inhibitors (as compared to baseline biopsies). Finally, CX3CR1+ TAMs had negative prognostic impact in patients with resectable HR+HER2- breast cancer from a clinical trial testing neoadjuvant PD-1 blockage followed by stereotactic body radiotherapy.
Taken together, these findings suggest that γδ T cells and CX3CR1+ TAMs may support clinical resistance to CDK4/6 inhibitors in at least some patients with HR+HER2- breast cancer.
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