{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:17:40Z","timestamp":1779139060800,"version":"3.51.4"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cancer is one of the leading causes of death worldwide. Treatment outcome is largely dictated by the tumor type, disease stage, and treatment success rates, but also by the variation among patients in endogenous anti-tumor responses. Studies indicate that the presence of neutrophils in the tumor microenvironment is associated with a worse patient outcome due to their ability to suppress local anti-tumor T cell activity. Our previous studies investigated the mechanisms by which neutrophils suppress and damage T cells to become smaller in size (small T cells), debilitating their effector activities. Several studies indicate a role for tumor-associated macrophages in scavenging damaged or dead cells. We hypothesized that the observed lack of small T cells in the TME by confocal microscopy is due to immediate uptake by macrophages. In this study, we confirmed that indeed only the smaller, damaged T cells are taken up by macrophages, once serum-opsonized. Damaged T cells opsonized with complement factor C3 fragments were phagocytosed by macrophages, resulting in almost instantaneous and highly efficient uptake of these small T cells. Inhibition of the complement receptors CR1, CR3 and CR4 expressed by macrophages completely blocked phagocytosis. By contrast, actively proliferating T cells (large T cells) were neither impaired in neutrophil-MDSC activity nor opsonized for phagocytosis by macrophages. Rapid removal of damaged T cells suggests a role of complement and macrophages within the tumor microenvironment to clear suppressed T cells in cancer patients.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1183180","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T05:05:07Z","timestamp":1684213507000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Efficient complement-mediated clearance of immunosuppressed T cells by macrophages"],"prefix":"10.3389","volume":"14","author":[{"given":"Angela A. F.","family":"Gankema","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charita","family":"Furumaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Fern\u00e1ndez-Hermira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Hoogenboezem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanke L.","family":"Matlung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"van Bruggen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taco W.","family":"Kuijpers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1126\/science.aaa8172","article-title":"The future of immune checkpoint therapy","volume":"348","author":"Sharma","year":"2015","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02100","article-title":"Plasticity in pro- and anti-tumor activity of neutrophils: shifting the balance","volume":"11","author":"Furumaya","year":"2020","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1111\/nyas.12469","article-title":"Myeloid-derived suppressor cell heterogeneity in human cancers","volume":"1319","author":"Solito","year":"2014","journal-title":"Ann N Y Acad Sci"},{"key":"B5","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s00262-008-0523-4","article-title":"Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy","volume":"58","author":"Diaz-Montero","year":"2009","journal-title":"Cancer Immunol Immunother"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13178","article-title":"Neutrophil interactions with T cells, platelets, endothelial cells, and of course tumor cells","volume":"314","author":"Segal","year":"2022","journal-title":"Immunol Rev"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.619925","article-title":"\u03b22 integrin signaling cascade in neutrophils: more than a single function","volume":"11","author":"Bouti","year":"2021","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/s41568-020-0281-y","article-title":"Neutrophil diversity and plasticity in tumour progression and therapy","volume":"20","author":"Jaillon","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00012.2018","article-title":"The neutrophil\u2019s role during health and disease","volume":"99","author":"Liew","year":"2019","journal-title":"Physiol Rev"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2019.00085","article-title":"Cell type specific roles of nf-kb linking inflamation and thrombosis","volume":"10","author":"Mussbacher","year":"2019","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019031609","article-title":"Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair","volume":"3","author":"Aarts","year":"2019","journal-title":"Blood Adv"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e12989","DOI":"10.1111\/eci.12989","article-title":"Neutrophils as myeloid-derived suppressor cells","volume":"48","author":"Aarts","year":"2018","journal-title":"Eur J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00448","article-title":"Granule protein processing and regulated secretion in neutrophils","volume":"5","author":"Sheshachalam","year":"2014","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2018.02499","article-title":"Reactive oxygen species as regulators of MDSC-mediated immune suppression","volume":"9","author":"Ohl","year":"2018","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/s41580-020-0232-1","article-title":"The clearance of dead cells by efferocytosis","volume":"21","author":"Boada-Romero","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0240-6","article-title":"Efferocytosis in health and disease","volume":"20","author":"Doran","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1022-2","article-title":"Targeting Tyro3, axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment","volume":"18","author":"Myers","year":"2019","journal-title":"Mol Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2014.10.026","article-title":"Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters","volume":"220","author":"Reis","year":"2015","journal-title":"Physiol Behav"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2021.06.003","article-title":"Differential expression of complement receptors CR1\/2 and CR4 by murine M1 and M2 macrophages","author":"Ghate","year":"2021","journal-title":"Mol Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/s41573-022-00520-5","article-title":"Macrophages as tools and targets in cancer therapy","volume":"21","author":"Mantovani","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017015008","article-title":"Red pulp macrophages in the human spleen are a distinct cell population with a unique expression of fc- g receptors","volume":"2","author":"Nagelkerke","year":"2018","journal-title":"Blood Adv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2007.00981.x","article-title":"Macrophage complement receptors and pathogen clearance","volume":"9","author":"van Lookeren Campagne","year":"2007","journal-title":"Cell Microbiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.710390","article-title":"Interaction between the complement system and infectious agents \u2013 a potential mechanistic link to neurodegeneration and dementia","volume":"15","author":"Shinjyo","year":"2021","journal-title":"Front Cell Neurosci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fcell.2021.624025","article-title":"Complement receptors and their role in leukocyte recruitment and phagocytosis","volume":"9","author":"Vandendriessche","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1923","article-title":"Complement: a key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1158\/2326-6066.CIR-20-0922","article-title":"Mechanisms driving neutrophil-induced t-cell immunoparalysis in ovarian cancer","volume":"9","author":"Emmons","year":"2021","journal-title":"Cancer Immunol Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/s41568-019-0210-0","article-title":"Context-dependent roles of complement in cancer","volume":"19","author":"Roumenina","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12935-019-1027-3","article-title":"Role of the complement system in the tumor microenvironment","volume":"19","author":"Zhang","year":"2019","journal-title":"Cancer Cell Int"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e122311","DOI":"10.1172\/jci.insight.122311","article-title":"Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment","volume":"4","author":"Singel","year":"2019","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.02.014","article-title":"Autocrine effects of tumor-derived complement","volume":"6","author":"Cho","year":"2014","journal-title":"Cell Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03351-7","article-title":"Tumor angiogenesis: causes, consequences, challenges and opportunities","volume":"77","author":"Lugano","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1159\/000514314","article-title":"Vascular permeability: regulation pathways and role in kidney diseases","volume":"145","author":"Cai","year":"2021","journal-title":"Nephron"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djt205","article-title":"Investigation of complement activation product C4d as a diagnostic and prognostic biomarker for lung cancer","volume":"105","author":"Ajona","year":"2013","journal-title":"J Natl Cancer Inst"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1183180\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T05:05:08Z","timestamp":1684213508000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1183180\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":33,"alternative-id":["10.3389\/fimmu.2023.1183180"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1183180","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,16]]},"article-number":"1183180"}}