Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression
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 effec...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/3/e005325.full |
| _version_ | 1827890650694025216 |
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| author | Sofia Bruni Florencia L Mauro Cecilia J Proietti Rosalia I Cordo-Russo Martin A Rivas Gloria Inurrigarro Agustina Dupont Dario Rocha Elmer A Fernández Ernesto Gil Deza Daniel Lopez Della Vecchia Sabrina Barchuk Silvina Figurelli David Lasso Adrián D Friedrich María C Santilli María V Regge Gabriel Lebersztein Claudio Levit Fabiana Anfuso Teresa Castiglione Patricia V Elizalde Maria F Mercogliano Roxana Schillaci |
| author_facet | Sofia Bruni Florencia L Mauro Cecilia J Proietti Rosalia I Cordo-Russo Martin A Rivas Gloria Inurrigarro Agustina Dupont Dario Rocha Elmer A Fernández Ernesto Gil Deza Daniel Lopez Della Vecchia Sabrina Barchuk Silvina Figurelli David Lasso Adrián D Friedrich María C Santilli María V Regge Gabriel Lebersztein Claudio Levit Fabiana Anfuso Teresa Castiglione Patricia V Elizalde Maria F Mercogliano Roxana Schillaci |
| author_sort | Sofia Bruni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T21:12:40Z |
| format | Article |
| id | doaj.art-260a8bffb8ab415c8e86847e61a3c8b1 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:12:40Z |
| publishDate | 2023-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-260a8bffb8ab415c8e86847e61a3c8b12023-07-30T08:30:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-03-0111310.1136/jitc-2022-005325Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppressionSofia Bruni0Florencia L Mauro1Cecilia J Proietti2Rosalia I Cordo-Russo3Martin A Rivas4Gloria Inurrigarro5Agustina Dupont6Dario Rocha7Elmer A Fernández8Ernesto Gil Deza9Daniel Lopez Della Vecchia10Sabrina Barchuk11Silvina Figurelli12David Lasso13Adrián D Friedrich14María C Santilli15María V Regge16Gabriel Lebersztein17Claudio Levit18Fabiana Anfuso19Teresa Castiglione20Patricia V Elizalde21Maria F Mercogliano22Roxana Schillaci23Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaDivision of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USAServicio de Patología, Sanatorio Mater Dei, Buenos Aires, ArgentinaServicio de Patología, Sanatorio Mater Dei, Buenos Aires, ArgentinaBioscience Data Mining Group at CIDIE-CONICET-UCC, Córdoba, ArgentinaBioscience Data Mining Group at CIDIE-CONICET-UCC, Córdoba, ArgentinaInstituto Oncológico Henry Moore, Buenos Aires, ArgentinaSección Patología Mamaria Hospital General de Agudos Juan A Fernández, Buenos Aires, ArgentinaSección Patología Mamaria Hospital General de Agudos Juan A Fernández, Buenos Aires, ArgentinaServicio de Patología, Hospital General de Agudos Juan A. Fernández,, Buenos Aires, ArgentinaHospital Oncológico Provincial de Córdoba, Córdoba, ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaServicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, ArgentinaServicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, ArgentinaServicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, ArgentinaCentro de Patología Dr Boris Elsner, Buenos Aires, ArgentinaLaboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaLaboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, ArgentinaBackground 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.https://jitc.bmj.com/content/11/3/e005325.full |
| spellingShingle | Sofia Bruni Florencia L Mauro Cecilia J Proietti Rosalia I Cordo-Russo Martin A Rivas Gloria Inurrigarro Agustina Dupont Dario Rocha Elmer A Fernández Ernesto Gil Deza Daniel Lopez Della Vecchia Sabrina Barchuk Silvina Figurelli David Lasso Adrián D Friedrich María C Santilli María V Regge Gabriel Lebersztein Claudio Levit Fabiana Anfuso Teresa Castiglione Patricia V Elizalde Maria F Mercogliano Roxana Schillaci Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression Journal for ImmunoTherapy of Cancer |
| title | Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression |
| title_full | Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression |
| title_fullStr | Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression |
| title_full_unstemmed | Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression |
| title_short | Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression |
| title_sort | blocking soluble tnfα sensitizes her2 positive breast cancer to trastuzumab through muc4 downregulation and subverts immunosuppression |
| url | https://jitc.bmj.com/content/11/3/e005325.full |
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