Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies

Autor: Ashraf, Yahya, Mansouri, Hanane, Laurent-Matha, Valérie, Alcaraz, Lindsay B., Roger, Pascal, Guiu, Séverine, Derocq, Danielle, Robin, Gautier, Michaud, Henri-Alexandre, Delpech, Helène, Jarlier, Marta, Pugnière, Martine, Robert, Bruno, Puel, Anthony, Martin, Lucie, Landomiel, Flavie, Bourquard, Thomas, Achour, Oussama, Fruitier-Arnaudin, Ingrid, Pichard, Alexandre, Deshayes, Emmanuel, Turtoi, Andrei, Poupon, Anne, Simony-Lafontaine, Joëlle, Boissière-Michot, Florence, Pirot, Nelly, Bernex, Florence, Jacot, William, du Manoir, Stanislas, Theillet, Charles, Pouget, Jean-Pierre, Navarro-Teulon, Isabelle, Bonnefoy, Nathalie, Pèlegrin, André, Chardès, Thierry, Martineau, Pierre, Liaudet-Coopman, Emmanuelle
Přispěvatelé: Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Institut du Cancer de Montpellier (ICM), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), LIttoral ENvironnement et Sociétés - UMR 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), French National Research Agency (ANR) as part of the 'Investissements d'Avenir' program [ANR-10-LABX-53-01], SIRIC Montpellier Cancer [INCa_In-serm_DGOS_12553], INSERM, INSERM Transfert, University of Montpellier, 'Labex MabImprove', CANCEROPOLE GSO [2014-E12], 'Ligue Regionale du Gard', 'Ligue Regionale de l'Herault', 'Ligue Regionale de la Charente Maritime', 'GEFLUC', FRM 'Fondation pour la Recherche Medicale', ARC 'Association pour la Recherche sur le Cancer', Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MAbSilico SAS, This work was supported by a public grant overseen by the French National Research Agency (ANR) as part of the 'Investissements d’Avenir' program (reference: ANR-10-LABX-53-01), SIRIC Montpellier Cancer Grant INCa_In-serm_DGOS_12553, INSERM, INSERM Transfert, University of Montpellier, the ‘Labex MabImprove’, the CANCEROPOLE GSO (2014-E12), the associations‘Ligue Régionale du Gard’, ‘Ligue Régionale de l’Herault’,‘Ligue Régionale de la Charente Maritime’,‘GEFLUC’, FRM ‘Fondation pour la Recherche Médicale’, and ARC‘Association pour la Recherche sur le Cancer., Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Chardès, Thierry, Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
[SDV.BIO]Life Sciences [q-bio]/Biotechnology
[SDV.IMM] Life Sciences [q-bio]/Immunology
biologie computationnelle
[SDV]Life Sciences [q-bio]
education
Mice
Nude
[SDV.CAN]Life Sciences [q-bio]/Cancer
Triple Negative Breast Neoplasms
[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
lcsh:RC254-282
Cathepsin D
Human antibody-based therapy
Immunomodulation
Antineoplastic Agents
Immunological
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Line
Tumor
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
Animals
Humans
RNA
Messenger
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
skin and connective tissue diseases
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
health care economics and organizations
[SDV.IB] Life Sciences [q-bio]/Bioengineering
Antibodies
Monoclonal
[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Xenograft Model Antitumor Assays
[SDV.BIO] Life Sciences [q-bio]/Biotechnology
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biomolecules [q-bio.BM]
Protease
Tumor Burden
Tumor microenvironment
[SDV.IMM]Life Sciences [q-bio]/Immunology
[SDV.IB]Life Sciences [q-bio]/Bioengineering
Female
Phage display
Immunotherapy
[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
TNBC
Research Article
Zdroj: Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer, London : BioMed Central, 2013-, 2019, 7 (1), pp.29-46. ⟨10.1186/s40425-019-0498-z⟩
Journal for Immunotherapy of Cancer, BMJ Publishing Group 2019, 7 (1), pp.29-46. ⟨10.1186/s40425-019-0498-z⟩
Journal for Immunotherapy of Cancer, BMJ Publishing Group 2019, 7, ⟨10.1186/s40425-019-0498-z⟩
Journal for Immunotherapy of Cancer, 2019, 7 (1), pp.29-46. ⟨10.1186/s40425-019-0498-z⟩
Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-17 (2019)
ISSN: 2051-1426
DOI: 10.1186/s40425-019-0498-z⟩
Popis: Background Triple-negative breast cancer (TNBC) treatment is currently restricted to chemotherapy. Hence, tumor-specific molecular targets and/or alternative therapeutic strategies for TNBC are urgently needed. Immunotherapy is emerging as an exciting treatment option for TNBC patients. The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (BC), is overproduced and hypersecreted by human BC cells. This study explores whether cath-D is a tumor cell-associated extracellular biomarker and a potent target for antibody-based therapy in TNBC. Methods Cath-D prognostic value and localization was evaluated by transcriptomics, proteomics and immunohistochemistry in TNBC. First-in-class anti-cath-D human scFv fragments binding to both human and mouse cath-D were generated using phage display and cloned in the human IgG1 λ format (F1 and E2). Anti-cath-D antibody biodistribution, antitumor efficacy and in vivo underlying mechanisms were investigated in TNBC MDA-MB-231 tumor xenografts in nude mice. Antitumor effect was further assessed in TNBC patient-derived xenografts (PDXs). Results High CTSD mRNA levels correlated with shorter recurrence-free survival in TNBC, and extracellular cath-D was detected in the tumor microenvironment, but not in matched normal breast stroma. Anti-cath-D F1 and E2 antibodies accumulated in TNBC MDA-MB-231 tumor xenografts, inhibited tumor growth and improved mice survival without apparent toxicity. The Fc function of F1, the best antibody candidate, was essential for maximal tumor inhibition in the MDA-MB-231 model. Mechanistically, F1 antitumor response was triggered through natural killer cell activation via IL-15 upregulation, associated with granzyme B and perforin production, and the release of antitumor IFNγ cytokine. The F1 antibody also prevented the tumor recruitment of immunosuppressive tumor-associated macrophages M2 and myeloid-derived suppressor cells, a specific effect associated with a less immunosuppressive tumor microenvironment highlighted by TGFβ decrease. Finally, the antibody F1 inhibited tumor growth of two TNBC PDXs, isolated from patients resistant or not to neo-adjuvant chemotherapy. Conclusion Cath-D is a tumor-specific extracellular target in TNBC suitable for antibody-based therapy. Immunomodulatory antibody-based strategy against cath-D is a promising immunotherapy to treat patients with TNBC. Electronic supplementary material The online version of this article (10.1186/s40425-019-0498-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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