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

Abstract : Background: Triple-negative breast cancer (TNBC) treatment is currently restricted to chemotherapy. Hence, tumorspecific 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 andimmunohistochemistry in TNBC. First-in-class anti-cath-D human scFv fragments binding to both human and mousecath-D were generated using phage display and cloned in the human IgG1λformat (F1 and E2). Anti-cath-D antibodybiodistribution, antitumor efficacy and in vivo underlying mechanisms were investigated in TNBC MDA-MB-231 tumorxenografts in nude mice. Antitumor effect was further assessed in TNBC patient-derived xenografts (PDXs). Results: HighCTSDmRNA levels correlated with shorter recurrence-free survival in TNBC, and extracellular cath-D wasdetected in the tumor microenvironment, but not in matched normal breast stroma. Anti-cath-D F1 and E2 antibodiesaccumulated in TNBC MDA-MB-231 tumor xenografts, inhibited tumor growth and improved mice survival withoutapparent toxicity. The Fc function of F1, the best antibody candidate, was essential for maximal tumor inhibition in theMDA-MB-231 model. Mechanistically, F1 antitumor response was triggered through natural killer cell activation via IL-15upregulation, associated with granzyme B and perforin production, and the release of antitumor IFNγcytokine. The F1antibody also prevented the tumor recruitment of immunosuppressive tumor-associated macrophages M2 andmyeloid-derived suppressor cells, a specific effect associated with a less immunosuppressive tumor microenvironmenthighlighted by TGFβdecrease. Finally, the antibody F1 inhibited tumor growth of two TNBC PDXs, isolated frompatients 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 withTNBC
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https://hal-cnrs.archives-ouvertes.fr/hal-03039856
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Submitted on : Friday, December 4, 2020 - 9:35:33 AM
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Yahya Ashraf, Hanane Mansouri, Valérie Laurent-Matha, Lindsay Alcaraz, Pascal Roger, et al.. Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies. Journal for Immunotherapy of Cancer, BMJ Publishing Group 2019, 7, ⟨10.1186/s40425-019-0498-z⟩. ⟨hal-03039856⟩

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