TY - JOUR T1 - Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression. AU - Bruni,Sofia, AU - Mauro,Florencia L, AU - Proietti,Cecilia J, AU - Cordo-Russo,Rosalia I, AU - Rivas,Martin A, AU - Inurrigarro,Gloria, AU - Dupont,Agustina, AU - Rocha,Dario, AU - Fernández,Elmer A, AU - Deza,Ernesto Gil, AU - Lopez Della Vecchia,Daniel, AU - Barchuk,Sabrina, AU - Figurelli,Silvina, AU - Lasso,David, AU - Friedrich,Adrián D, AU - Santilli,María C, AU - Regge,María V, AU - Lebersztein,Gabriel, AU - Levit,Claudio, AU - Anfuso,Fabiana, AU - Castiglione,Teresa, AU - Elizalde,Patricia V, AU - Mercogliano,Maria F, AU - Schillaci,Roxana, PY - 2023/02/21/accepted PY - 2023/3/8/entrez PY - 2023/3/9/pubmed PY - 2023/3/11/medline KW - Breast Neoplasms KW - Drug Therapy, Combination KW - Immune Evation KW - Lymphocytes, Tumor-Infiltrating KW - Macrophages JF - Journal for immunotherapy of cancer JO - J Immunother Cancer VL - 11 IS - 3 N2 - BACKGROUND: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion. METHODS: We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes. RESULTS: In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors. CONCLUSIONS: These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance. SN - 2051-1426 UR - https://www.unboundmedicine.com/medline/citation/36889811/Blocking_soluble_TNF DB - PRIME DP - Unbound Medicine ER -