{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:11:42Z","timestamp":1790809902633,"version":"4.1.0"},"reference-count":49,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"SIRIC SOCRATE 2.0","award":["INCa-DGOS-INSERM\/12551"],"award-info":[{"award-number":["INCa-DGOS-INSERM\/12551"]}]},{"DOI":"10.13039\/100017729","name":"Philanthropia Foundation","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100017729","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004099","name":"La Ligue Nationale Contre le Cancer","doi-asserted-by":"crossref","award":["Equipe labellis\u00e9e EL2018_Kannouche"],"award-info":[{"award-number":["Equipe labellis\u00e9e EL2018_Kannouche"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"crossref"}]},{"name":"SIRIC SOCRATE","award":["INCa-DGOS-INSERM\/6043"],"award-info":[{"award-number":["INCa-DGOS-INSERM\/6043"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,6,30]]},"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Clinical studies have highlighted the efficacy of anti-programmed death 1 (\u03b1PD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to \u03b1PD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD gene <jats:italic>Msh2,<\/jats:italic> 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 \u03b1PD-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 \u03b1LY6G antibody, and regulatory T (Treg) cell population was reduced with \u03b1CD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (\u03b1CTLA-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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 \u03b1PD-1 monotherapy. Importantly, depletion of TIN using \u03b1Ly-6G antibody reduced Treg cells and restored \u03b1PD-1 response. Conversely, targeting Treg cells by \u03b1CD25 or \u03b1CTLA-4 antibodies limited peripheral TIN accumulation and elicited response in \u03b1PD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, \u03b1PD-1+\u03b1CTLA-4 combination overcomes TIN-induced resistance to \u03b1PD-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 \u03b1PD-1 therapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>TIN countered \u03b1PD-1 efficacy in MMRD tumors. Since \u03b1CTLA-4 could restrict TIN accumulation, \u03b1PD-1+\u03b1CTLA-4 combination overcomes \u03b1PD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005059","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T01:54:43Z","timestamp":1658973283000},"page":"e005059","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Overcoming resistance to \u03b1PD-1 of MMR-deficient tumors with high tumor-induced neutrophils levels by combination of \u03b1CTLA-4 and \u03b1PD-1 blockers"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8915-7052","authenticated-orcid":false,"given":"Laetitia","family":"Nebot-Bral","sequence":"first","affiliation":[{"name":"CNRS-UMR9019, Equipe labellis\u00e9e Ligue Contre le Cancer, Gustave Roussy, Universit\u00e9 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