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

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

  • Nat Cancer. 2025 Oct;6(10):1656-1675. doi: 10.1038/s43018-025-01007-z.
Giulia Petroni # 1 2,  Claudia Galassi # 1,  Kenneth H Gouin 3rd # 3,  Hsiang-Han Chen 3 4,  Aitziber Buqué 1,  Norma Bloy 1,  Takahiro Yamazaki 1,  Ai Sato 1,  Manuel Beltrán-Visiedo 1,  Ginevra Campia 1,  Carlos Jiménez-Cortegana 1 5,  Aagam Shah 3,  Alexander Kirchmair 6,  Chiara Massa 7,  Claudia Wickenhauser 8,  Carlos Eduardo de Andrea 9,  Belén Navarro-Rubio 10,  Irantzu Serrano-Mendioroz 11,  Esther Navarro Manzano 12 13,  Alexandra M Satty 14,  Brady Rippon 15,  Francesca Finotello 6 16 17,  Zlatko Trajanoski 6,  Xi Kathy Zhou 15,  Joseph M Scandura 14,  Elena García-Martínez 13 18 19,  Francisco Ayala de la Peña 13 18 20,  María Esperanza Rodríguez-Ruiz 10 11,  Barbara Seliger 7 21 22,  Víctor Sánchez-Margalet 5 23,  Luis de la Cruz-Merino 5 24,  Reva K Basho 25,  Stephen L Shiao 3 26,  Heather L McArthur 27,  Silvia C Formenti 28 29 30,  Simon R V Knott 31,  Lorenzo Galluzzi 32 33 34 35
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
  • 2 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • 3 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 4 Department of Computer Science and Information Engineering, National Taiwan Normal University, Taipei, Taiwan.
  • 5 Department of Medical Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, Universidad de Sevilla, Sevilla, Spain.
  • 6 Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.
  • 7 Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • 8 Institute of Pathology, University Hospital Halle, Halle, Germany.
  • 9 Department of Anatomy, Physiology and Pathology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 10 Department of Radiation Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 11 Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain.
  • 12 Centro Regional de Hemodonación, Murcia, Spain.
  • 13 Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain.
  • 14 Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 15 Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
  • 16 Department of Molecular Biology, University of Innsbruck, Innsbruck, Austria.
  • 17 Digital Science Center (DiSC), University of Innsbruck, Innsbruck, Austria.
  • 18 Department of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer, Murcia, Spain.
  • 19 Universidad Católica San Antonio de Murcia, Guadalupe, Spain.
  • 20 Universidad de Murcia, Murcia, Spain.
  • 21 Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
  • 22 Institute for Translational Immunology, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany.
  • 23 Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen Macarena/CSIC/Universidad de Sevilla, Department of Clinical Oncology, Hospital Universitario de la Virgen Macarena, Sevilla, Spain.
  • 24 Department of Clinical Oncology, Hospital Universitario de la Virgen Macarena, Sevilla, Spain.
  • 25 Ellison Institute of Technology, Los Angeles, CA, USA.
  • 26 Department of Radiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 27 Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
  • 28 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. [email protected].
  • 29 Department of Medicine, Weill Cornell Medicine, New York, NY, USA. [email protected].
  • 30 Sandra and Edward Meyer Cancer Center, New York, NY, USA. [email protected].
  • 31 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [email protected].
  • 32 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. [email protected].
  • 33 Sandra and Edward Meyer Cancer Center, New York, NY, USA. [email protected].
  • 34 Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA. [email protected].
  • 35 Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA. [email protected].
  • # Contributed equally.
PMID: 40624238 DOI: 10.1038/s43018-025-01007-z
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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