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

Autor:	Bruni S; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Mauro FL; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Proietti CJ; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Cordo-Russo RI; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Rivas MA; Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Inurrigarro G; Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina., Dupont A; Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina., Rocha D; Bioscience Data Mining Group at CIDIE-CONICET-UCC, Córdoba, Argentina., Fernández EA; Bioscience Data Mining Group at CIDIE-CONICET-UCC, Córdoba, Argentina., Deza EG; Instituto Oncológico Henry Moore, Buenos Aires, Argentina., Lopez Della Vecchia D; Sección Patología Mamaria Hospital General de Agudos 'Juan A Fernández, Buenos Aires, Argentina., Barchuk S; Sección Patología Mamaria Hospital General de Agudos 'Juan A Fernández, Buenos Aires, Argentina., Figurelli S; Servicio de Patología, Hospital General de Agudos 'Juan A. Fernández,', Buenos Aires, Argentina., Lasso D; Hospital Oncológico Provincial de Córdoba, Córdoba, Argentina., Friedrich AD; Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Santilli MC; Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Regge MV; Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Lebersztein G; Servicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, Argentina., Levit C; Servicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, Argentina., Anfuso F; Servicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, Argentina., Castiglione T; Centro de Patología Dr Boris Elsner, Buenos Aires, Argentina., Elizalde PV; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Mercogliano MF; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Schillaci R; Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina roxanaschillaci@gmail.com.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Mar; Vol. 11 (3).
DOI:	10.1136/jitc-2022-005325
Abstrakt:	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. Competing Interests: Competing interests: RS is a consultant for and a research grant from INmune Bio. All other authors declare they have no competing interests. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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