Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors

Elisa I. Rivas, Jenniffer Linares, Melissa Zwick, Andrea Gómez-Llonin, Marc Guiu, Anna Labernadie, Jordi Badia-Ramentol, Anna Lladó, Lídia Bardia, Iván Pérez-Núñez, Carolina Martínez-Ciarpaglini, Noelia Tarazona, Anna Sallent-Aragay, Marta Garrido, Toni Celià-Terrassa, Octavio Burgués, Roger R. Gomis, Joan Albanell and Alexandre Calon ()
Additional contact information
Elisa I. Rivas: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Jenniffer Linares: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Melissa Zwick: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Andrea Gómez-Llonin: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Marc Guiu: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)
Anna Labernadie: Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute for Science and Technology (BIST)
Jordi Badia-Ramentol: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Anna Lladó: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)
Lídia Bardia: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)
Iván Pérez-Núñez: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Carolina Martínez-Ciarpaglini: Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia
Noelia Tarazona: Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia
Anna Sallent-Aragay: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Marta Garrido: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Toni Celià-Terrassa: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Octavio Burgués: Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia
Roger R. Gomis: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)
Joan Albanell: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)
Alexandre Calon: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM)

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients’ response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

Date: 2022
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DOI: 10.1038/s41467-022-32782-3

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