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

Overview

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.

authors

  • Petroni, Giulia
  • Galassi, Claudia
  • Gouin, Kenneth H
  • Chen, Hsiang-Han
  • Buqué, Aitziber
  • Bloy, Norma
  • Yamazaki, Takahiro
  • Sato, Ai
  • Beltrán-Visiedo, Manuel
  • Campia, Ginevra
  • Jiménez-Cortegana, Carlos
  • Shah, Aagam
  • Kirchmair, Alexander
  • Massa, Chiara
  • Wickenhauser, Claudia
  • de Andrea, Carlos Eduardo
  • Navarro-Rubio, Belén
  • Serrano-Mendioroz, Irantzu
  • Navarro Manzano, Esther
  • Satty, Alexandra M
  • Rippon, Brady
  • Finotello, Francesca
  • Trajanoski, Zlatko
  • Zhou, Xi Kathy
  • Scandura, Joseph M
  • García-Martínez, Elena
  • Ayala de la Peña, Francisco
  • Rodríguez-Ruiz, María Esperanza
  • Seliger, Barbara
  • Sánchez-Margalet, Víctor
  • de la Cruz-Merino, Luis
  • Basho, Reva K
  • Shiao, Stephen L
  • McArthur, Heather L
  • Formenti, Silvia Chiara
  • Knott, Simon R V
  • Galluzzi, Lorenzo

publication date

  • July 7, 2025

Identity

Digital Object Identifier (DOI)

  • 10.1038/s43018-025-01007-z

PubMed ID

  • 40624238