{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:53:20Z","timestamp":1792497200113,"version":"4.5.0"},"reference-count":58,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T00:00:00Z","timestamp":1646784000000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005039","name":"Leids Universitair Medisch Centrum","doi-asserted-by":"publisher","award":["MD\/PhD grant - Tom Harryvan"],"award-info":[{"award-number":["MD\/PhD grant - Tom Harryvan"]}],"id":[{"id":"10.13039\/501100005039","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["KWF grant 2017-10815"],"award-info":[{"award-number":["KWF grant 2017-10815"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["VIDI grant 192.011"],"award-info":[{"award-number":["VIDI grant 192.011"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,2,2]]},"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T\u2009cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T\u2009cell function is unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR\/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-003591","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T11:19:53Z","timestamp":1646824793000},"page":"e003591","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0386-8302","authenticated-orcid":false,"given":"Tom J","family":"Harryvan","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9onie","family":"Plug","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Griffioen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7805-7064","authenticated-orcid":false,"given":"Arend","family":"Mulder","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7898-9408","authenticated-orcid":false,"given":"Peter A","family":"van Veelen","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The 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