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

ABSTRACT: Resistance to CDK4/6 inhibitors leads to treatment failure and disease progression in women with HR+HER2- breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting IL17A-secreting γδ T cells to mouse HR+HER2- BCs upon CDK4/6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of HR+HER2- BC patients. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of patients with HR+HER2- BC receiving CDK4/6 inhibitors. Intratumoral γδ T cells were increased in post- vs pre-treatment biopsies from HR+HER2- BC patients relapsing on CDK4/6 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 CDK4/6 inhibitors in HR+HER2- BC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296805 | GEO | 2025/05/09

REPOSITORIES: GEO

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

Project description:Resistance to CDK4/6 inhibitors leads to treatment failure and disease progression in women with HR+HER2- breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting IL17A-secreting γδ T cells to mouse HR+HER2- BCs upon CDK4/6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) towards an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of HR+HER2- BC patients. Circulating γδ T cells and plasma CCL2 levels negatively correlated with progression in an independent series of patients with HR+HER2- BC receiving CDK4/6 inhibitors. Intratumoral γδ T cells were increased in post- vs pre-treatment biopsies from HR+HER2- BC patients relapsing on CDK4/6 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 CDK4/6 inhibitors in HR+HER2- BC patients.

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