دورية أكاديمية
Overcoming resistance to αPD-1 of MMR-deficient tumors with high tumor-induced neutrophils levels by combination of αCTLA-4 and αPD-1 blockers.
| العنوان: | Overcoming resistance to αPD-1 of MMR-deficient tumors with high tumor-induced neutrophils levels by combination of αCTLA-4 and αPD-1 blockers. |
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| المؤلفون: | Nebot-Bral L; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Hollebecque A; Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, F-94805, Villejuif, France., Yurchenko AA; INSERM-U981, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., de Forceville L; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Danjou M; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Jouniaux JM; Laboratoire d'Immunomonitoring en Oncologie, Unité US-23 INSERM, UMS-3655 CNRS, Gustave Roussy, F-94805 Villejuif, France., Rosa RCA; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Pouvelle C; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Aoufouchi S; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Vuagnat P; Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, F-94805, Villejuif, France., Smolenschi C; Département de médecine oncologique, Gustave Roussy, F-94805 Villejuif, France., Colomba E; Département de médecine oncologique, Gustave Roussy, F-94805 Villejuif, France., Leary A; Département de médecine oncologique, Gustave Roussy, F-94805 Villejuif, France., Marabelle A; Département d'Innovation Thérapeutique et d'Essais Précoces, Gustave Roussy, F-94805, Villejuif, France.; Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France., Scoazec JY; Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.; Département de Biologie et pathologie médicales, Gustave Roussy, F-94805 Villejuif, France., Cassard L; Laboratoire d'Immunomonitoring en Oncologie, Unité US-23 INSERM, UMS-3655 CNRS, Gustave Roussy, F-94805 Villejuif, France., Nikolaev S; INSERM-U981, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France., Chaput N; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France nathalie.chaput@gustaveroussy.fr.; Laboratoire d'Immunomonitoring en Oncologie, Unité US-23 INSERM, UMS-3655 CNRS, Gustave Roussy, F-94805 Villejuif, France.; Faculté de Pharmacie, Université Paris-Saclay, 91400 Orsay, France., Kannouche P; CNRS-UMR9019, Equipe labellisée Ligue Contre le Cancer, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France. |
| المصدر: | Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jul; Vol. 10 (7). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd. Original Publication: London : BioMed Central, 2013- |
| مواضيع طبية MeSH: | Neutrophils*, Animals ; Humans ; Mice ; Brain Neoplasms ; Colorectal Neoplasms ; Microsatellite Instability ; Neoplastic Syndromes, Hereditary ; Retrospective Studies ; Tumor Microenvironment |
| مستخلص: | Background: Clinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood. Methods: 4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene Msh2, leading to a massive accumulation of mutations after serial passages of cells. Insertions/deletion events and mutation load were evaluated by whole exome sequencing. Mice bearing highly mutated MMRD tumor or parental tumors were treated with αPD-1 and tumor volume was monitored. Immune cell type abundance was dynamically assessed in the tumor microenvironment and the blood by flow cytometry. Neutrophils were depleted in mice using αLY6G antibody, and regulatory T (Treg) cell population was reduced with αCD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (αCTLA-4) antibodies. Patients with MMRD tumors treated with immune checkpoint blockade-based therapy were retrospectively identified and neutrophil-to-lymphocyte ratio (NLR) was evaluated and examined for correlation with clinical benefit. Results: By recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy. Conclusions: TIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation. Competing Interests: Competing interests: NC reports grants from Cytune Pharma, grants from BMS, grants from SANOFI, personal fees from AstraZeneca France, outside the submitted work. Other authors declare no conflict of interest with this work. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) |
| التعليقات: | Erratum in: J Immunother Cancer. 2022 Aug;10(8):. (PMID: 36002190) |
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| فهرسة مساهمة: | Keywords: CTLA-4 antigen; genome instability; immunotherapy; neutrophil infiltration; tumor biomarkers |
| SCR Disease Name: | Turcot syndrome |
| تواريخ الأحداث: | Date Created: 20220727 Date Completed: 20230914 Latest Revision: 20230914 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9335020 |
| DOI: | 10.1136/jitc-2022-005059 |
| PMID: | 35896284 |
| قاعدة البيانات: | MEDLINE |
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