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

Giulia Petroni^#^{1

2}, Claudia Galassi^#¹, Kenneth H Gouin 3rd^#³, Hsiang-Han Chen^{3

4}, Aitziber Buqué¹, Norma Bloy¹, Takahiro Yamazaki¹, Ai Sato¹, Manuel Beltrán-Visiedo¹, Ginevra Campia¹, Carlos Jiménez-Cortegana^{1

5}, Aagam Shah³, Alexander Kirchmair⁶, Chiara Massa⁷, Claudia Wickenhauser⁸, Carlos Eduardo de Andrea⁹, Belén Navarro-Rubio¹⁰, Irantzu Serrano-Mendioroz¹¹, Esther Navarro Manzano^{12

13}, Alexandra M Satty¹⁴, Brady Rippon¹⁵, Francesca Finotello^{6

16

17}, Zlatko Trajanoski⁶, Xi Kathy Zhou¹⁵, Joseph M Scandura¹⁴, 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 Basho²⁵, Stephen L Shiao^{3

26}, Heather L McArthur²⁷, Silvia C Formenti^{28

29

30}, Simon R V Knott³¹, 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. deadoc80@gmail.com.
²⁹ Department of Medicine, Weill Cornell Medicine, New York, NY, USA. deadoc80@gmail.com.
³⁰ Sandra and Edward Meyer Cancer Center, New York, NY, USA. deadoc80@gmail.com.
³¹ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. formenti@med.cornell.edu.
³² Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. simon.knott@cshs.org.
³³ Sandra and Edward Meyer Cancer Center, New York, NY, USA. simon.knott@cshs.org.
³⁴ Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA. simon.knott@cshs.org.
³⁵ Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA. simon.knott@cshs.org.

^# Contributed equally.

PMID: 40624238
DOI: 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

Giulia Petroni et al. Nat Cancer. 2025.

. 2025 Jul 7.

doi: 10.1038/s43018-025-01007-z. Online ahead of print.

Authors

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. deadoc80@gmail.com.
²⁹ Department of Medicine, Weill Cornell Medicine, New York, NY, USA. deadoc80@gmail.com.
³⁰ Sandra and Edward Meyer Cancer Center, New York, NY, USA. deadoc80@gmail.com.
³¹ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. formenti@med.cornell.edu.
³² Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. simon.knott@cshs.org.
³³ Sandra and Edward Meyer Cancer Center, New York, NY, USA. simon.knott@cshs.org.
³⁴ Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA. simon.knott@cshs.org.
³⁵ Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA. simon.knott@cshs.org.

^# Contributed equally.

PMID: 40624238
DOI: 10.1038/s43018-025-01007-z

Erratum in

Author Correction: 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 KH 3rd, Chen HH, Buqué A, Bloy N, Yamazaki T, Sato A, Beltrán-Visiedo M, Campia G, Jiménez-Cortegana C, Shah A, Kirchmair A, Massa C, Wickenhauser C, de Andrea CE, Navarro-Rubio B, Serrano-Mendioroz I, Navarro Manzano E, Satty AM, Rippon B, Finotello F, Trajanoski Z, Zhou XK, Scandura JM, García-Martínez E, Ayala de la Peña F, Rodríguez-Ruiz ME, Seliger B, Sánchez-Margalet V, de la Cruz-Merino L, Basho RK, Shiao SL, McArthur HL, Formenti SC, Knott SRV, Galluzzi L. Petroni G, et al. Nat Cancer. 2025 Jul 23. doi: 10.1038/s43018-025-01036-8. Online ahead of print. Nat Cancer. 2025. PMID: 40702362 No abstract available.

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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Conflict of interest statement

Competing interests: F.F. has been holding research contracts with iOnctura. M.E.R.-R. reports receiving research funding from Roche and Bioncotech. She also has received speaker’s bureau honoraria from Bristol Myers Squibb (BMS) and Roche. H.L.M. is/has been holding research contracts with BMS, MedImmune, LLC/AstraZeneca, BTG and Merck and has received consulting/advisory honoraria from Amgen, BMS, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience and TapImmune. S.C.F. is/has been holding research contracts with Merck, Varian, BMS, Celldex, Regeneron, Eisai and Eli Lilly and has received consulting/advisory honoraria from Bayer, BMS, Varian, Elekta, Regeneron, Eisai, AstraZeneca, MedImmune, Merck US, EMD Serono, Accuray, Boehringer Ingelheim, Roche, Genentech, AstraZeneca, View Ray and Nanobiotix. S.R.V.K. is a founder and consultant at Transomic Technologies and Faeth Therapeutics. L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation and holds Promontory stock options. All other authors have no conflicts to declare.

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

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