Paralysis of the cytotoxic granule machinery is a new cancer immune evasion mechanism mediated by chitinase 3-like-1
| Autor: | Maria Rescigno, Abbass Darwich, Hannah Obeck, Claudio Sustmann, Alexandre Taleb, Giuseppe Curigliano, Giovanna Masci, Lapo Morelli, Sebastian Kobold, M. Benmebarek, Alessia Melacarne, Domenico Supino, Alessandra Silvestri, Agnese Losurdo, Giuseppe Penna, Bruno L. Cadilha, Juliette Mouriès |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
medicine.medical_treatment Immunology Immunological synapse Mice Immune system Neoplasms medicine Immunology and Allergy Cytotoxic T cell Animals Humans Chitinase-3-Like Protein 1 Cytotoxicity RC254-282 Immune Evasion Pharmacology Antibody-dependent cell-mediated cytotoxicity Chemistry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunotherapy Killer Cells Natural Oncology Tumor Escape Lytic cycle Cancer research Molecular Medicine Female |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 11 (2021) Journal for the Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | BackgroundNatural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms.MethodsNK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models.ResultsWe found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts.ConclusionOur work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies. |
| Databáze: | OpenAIRE |
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