by Keyword: enrichment analysis
Rivas, 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, (2022). Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors Nature Communications 13, 5310 
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.
JTD Keywords: activation, cells, efficacy, enrichment analysis, expression, infiltrating lymphocytes, survival, therapy, trastuzumab, Her2-positive breast-cancer
