Rivas, ElisaLinares Aceituno, Jenniffer LissetheZwick, MelissaGómez-Llonín, AndreaGuiu, MarcLabernadie, AnnaBadia-Ramentol, JordiLladó, AnnaBardia, LídiaPérez-Núñez, IvánMartínez-Ciarpaglini, CarolinaTarazona, NoeliaSallent-Aragay, AnnaGarrido, MartaCelià-Terrassa, ToniBurgués, OctavioGomis, Roger R.Albanell Mestres, JoanCalon, Alexandre2023-02-082023-02-082022Rivas EI, Linares J, Zwick M, Gómez-Llonin A, Guiu M, Labernadie A, Badia-Ramentol J, Lladó A, Bardia L, Pérez-Núñez I, Martínez-Ciarpaglini C, Tarazona N, Sallent-Aragay A, Garrido M, Celià-Terrassa T, Burgués O, Gomis RR, Albanell J, Calon A. Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors. Nat Commun. 2022 Sep 9;13(1):5310. DOI: 10.1038/s41467-022-32782-32041-1723http://hdl.handle.net/10230/55673About 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.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-022-32782-3Breast cancerCancer microenvironmentPredictive markersinfo:eu-repo/semantics/openAccess