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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

Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression

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  • Medientyp: E-Artikel
  • Titel: Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression
  • Beteiligte: 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
  • Erschienen: BMJ, 2023
  • Erschienen in: Journal for ImmunoTherapy of Cancer, 11 (2023) 3, Seite e005325
  • Sprache: Englisch
  • DOI: 10.1136/jitc-2022-005325
  • ISSN: 2051-1426
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: BackgroundThe 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.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.
  • Zugangsstatus: Freier Zugang