IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HR+HER2- breast cancer via CX3CR1+ macrophages PMID: 40624238

Target-related Cytokines

2026-09-23

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

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.

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.