Rivas and Linares et al. investigated resistance mechanisms associated with relapsed HER2-targeted therapy in two independent cohorts of patients with HER2+ breast cancer (BC) treated with trastuzumab. To dissect the TME’s role, a fully human immunocompetent ex vivo HER2+ BC model was developed, which revealed an enriched TGFβ-activated population of cancer-associated fibroblasts (FAP+ subtypes S1 and podoplanin+) with low IL-2 activity in therapy-resistant tumors. Combining trastuzumab with a targeted FAP–IL-2 fusion protein enhanced ADCC in HER2+ BC ex vivo and induced a strong NK cell-mediated anti-cancer response.
Contributed by Katherine Turner
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.
Author Info: (1) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. (2)Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of
Author Info: (1) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. (2)Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. (3) Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute for Science and Technology (BIST), Barcelona, Spain. (4) Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain. (5) Medical Oncology Department, Hospital del Mar, Barcelona, Spain. (6) Universitat Pompeu Fabra, Barcelona, Spain. (7) Centro de Investigación Biomédica en Red de Oncología (CIBERONC-ISCIII), Madrid, Spain. (8) Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. acalon@imim.es. #Contributed equally.
