Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression. Issue 3 (8th March 2023)

• Record Type: Journal Article
• Authors: Bruni, Sofia; Mauro, Florencia L; Proietti, Cecilia J; Cordo-Russo, Rosalia I; Rivas, Martin A; Inurrigarro, Gloria; Dupont, Agustina; Rocha, Dario; Fernández, Elmer A; Deza, Ernesto Gil; Lopez Della Vecchia, Daniel; Barchuk, Sabrina; Figurelli, Silvina; Lasso, David; Friedrich, Adrián D; Santilli, María C; Regge, María V; Lebersztein, Gabriel; Levit, Claudio; Anfuso, Fabiana; Castiglione, Teresa; Elizalde, Patricia V; Mercogliano, Maria F; Schillaci, Roxana
• Is Part Of: Journal for immunotherapy of cancer. Volume 11:Issue 3(2023)
• Publication Date: 2023-03-08
• Subjects: Breast Neoplasms -- Drug Therapy, Combination -- Immune Evation -- Lymphocytes, Tumor-Infiltrating -- Macrophages; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-005325
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.