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.
IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HR+HER2− breast cancer via CX3CR1+ macrophages / Petroni G.; Galassi C.; Gouin K.H.; Chen H.-H.; Buque A.; Bloy N.; Yamazaki T.; Sato A.; Beltran-Visiedo M.; Campia G.; Jimenez-Cortegana C.; Shah A.; Kirchmair A.; Massa C.; Wickenhauser C.; de Andrea C.E.; Navarro-Rubio B.; Serrano-Mendioroz I.; Navarro Manzano E.; Satty A.M.; Rippon B.; Finotello F.; Trajanoski Z.; Zhou X.K.; Scandura J.M.; Garcia-Martinez E.; Ayala de la Pena F.; Rodriguez-Ruiz M.E.; Seliger B.; Sanchez-Margalet V.; de la Cruz-Merino L.; Basho R.K.; Shiao S.L.; McArthur H.L.; Formenti S.C.; Knott S.R.V.; Galluzzi L.. - In: NATURE CANCER. - ISSN 2662-1347. - ELETTRONICO. - 6:(2025), pp. 1656-1675. [10.1038/s43018-025-01007-z]
IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HR+HER2− breast cancer via CX3CR1+ macrophages
Petroni G.;Galassi C.;Galluzzi L.
2025
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.
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