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

Abstract

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.