{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:52:09Z","timestamp":1793238729643,"version":"4.5.0"},"reference-count":58,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000},"content-version":"unspecified","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["UU-10660"],"award-info":[{"award-number":["UU-10660"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,9,30]]},"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade (ICB). However, resistance to ICB is commonly observed, and is associated with the presence of peritoneal-metastases and ascites formation. The mechanisms underlying this site-specific benefit of ICB are unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We created a novel model for spontaneous multiorgan metastasis in MSI-H CRC tumors by transplanting patient-derived organoids (PDO) into the cecum of humanized mice. Anti-programmed cell death protein-1 (PD-1) and anti-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) ICB treatment effects were analyzed in relation to the immune context of primary tumors, liver metastases, and peritoneal metastases. Immune profiling was performed by immunohistochemistry, flow cytometry and single-cell RNA sequencing. The role of B cells was assessed by antibody-mediated depletion. Immunosuppressive cytokine levels (interleukin (IL)-10, transforming growth factor (TGF)b1, TGFb2, TGFb3) were determined in ascites and serum samples by ELISA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>PDO-initiated primary tumors spontaneously metastasized to the liver and the peritoneum. Peritoneal-metastasis formation was accompanied by the accumulation of ascites. ICB completely cleared liver metastases and reduced primary tumor mass but had no effect on peritoneal metastases. This mimics clinical observations. After therapy discontinuation, primary tumor masses progressively decreased, but peritoneal metastases displayed unabated growth. Therapy efficacy correlated with the formation of tertiary lymphoid structures (TLS)\u2014containing B cells and juxtaposed T cells\u2014and with expression of an interferon-\u03b3 signature together with the B cell chemoattractant CXCL13. B cell depletion prevented liver-metastasis clearance by anti-CTLA-4 treatment. Peritoneal metastases were devoid of B cells and TLS, while the T cells in these lesions displayed a dysfunctional phenotype. Ascites samples from patients with cancer with peritoneal metastases and from the mouse model contained significantly higher levels of IL-10, TGFb1, TGFb2 and TGFb3 than serum samples.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>By combining organoid and humanized mouse technologies, we present a novel model for spontaneous multiorgan metastasis by MSI-H CRC, in which the clinically observed organ site-dependent benefit of ICB is recapitulated. Moreover, we provide empirical evidence for a critical role for B cells in the generation of site-dependent antitumor immunity following anti-CTLA-4 treatment. High levels of immunosuppressive cytokines in ascites may underlie the observed resistance of peritoneal metastases to ICB.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005345","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T10:47:41Z","timestamp":1671619661000},"page":"e005345","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":70,"title":["Modeling resistance of colorectal peritoneal metastases to immune checkpoint blockade in humanized mice"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-9464","authenticated-orcid":false,"given":"Emre","family":"K\u00fc\u00e7\u00fckk\u00f6se","sequence":"first","affiliation":[{"name":"Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2909-8481","authenticated-orcid":false,"given":"Balthasar A","family":"Heesters","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Utrecht University Faculty of Science, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Villaudy","sequence":"additional","affiliation":[{"name":"J&S Preclinical Solutions, Oss, The Netherlands"},{"name":"AIMM Therapeutics, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Verheem","sequence":"additional","affiliation":[{"name":"Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina","family":"Cercel","sequence":"additional","affiliation":[{"name":"AIMM Therapeutics, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"van Hal","sequence":"additional","affiliation":[{"name":"AIMM Therapeutics, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia F","family":"Boj","sequence":"additional","affiliation":[{"name":"Hubrecht Organoid Technology, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inne H M","family":"Borel Rinkes","sequence":"additional","affiliation":[{"name":"Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis J A","family":"Punt","sequence":"additional","affiliation":[{"name":"Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine M L","family":"Roodhart","sequence":"additional","affiliation":[{"name":"Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamila","family":"Laoukili","sequence":"additional","affiliation":[{"name":"Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Koopman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hergen","family":"Spits","sequence":"additional","affiliation":[{"name":"AIMM Therapeutics, Amsterdam, The Netherlands"},{"name":"Experimental Immunology, Amsterdam University Medical Centres, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2112-4390","authenticated-orcid":false,"given":"Onno","family":"Kranenburg","sequence":"additional","affiliation":[{"name":"Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"Utrecht Platform for Organoid Technology, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"2025100303494924000_10.12.e005345.1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0332"},{"key":"2025100303494924000_10.12.e005345.2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2016.161"},{"key":"2025100303494924000_10.12.e005345.3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.26086"},{"key":"2025100303494924000_10.12.e005345.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0275-8"},{"key":"2025100303494924000_10.12.e005345.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0805-8"},{"key":"2025100303494924000_10.12.e005345.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.76.9901"},{"key":"2025100303494924000_10.12.e005345.7","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30422-9"},{"key":"2025100303494924000_10.12.e005345.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500596"},{"key":"2025100303494924000_10.12.e005345.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2017699"},{"key":"2025100303494924000_10.12.e005345.10","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/djx136","article-title":"The balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors","volume":"110","author":"Marisa","year":"2018","journal-title":"J Natl Cancer Inst"},{"key":"2025100303494924000_10.12.e005345.11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.04.671"},{"key":"2025100303494924000_10.12.e005345.12","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2021.01.002","article-title":"Meta-Analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition","volume":"184","author":"Litchfield","year":"2021","journal-title":"Cell"},{"key":"2025100303494924000_10.12.e005345.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0057-z"},{"key":"2025100303494924000_10.12.e005345.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1922-8"},{"key":"2025100303494924000_10.12.e005345.15","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita","year":"2020","journal-title":"Nature"},{"key":"2025100303494924000_10.12.e005345.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1906-8"},{"key":"2025100303494924000_10.12.e005345.17","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41586-018-0694-x","article-title":"Lineage tracking reveals dynamic relationships of T cells in colorectal cancer","volume":"564","author":"Zhang","year":"2018","journal-title":"Nature"},{"key":"2025100303494924000_10.12.e005345.18","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.ccell.2021.05.006","article-title":"Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T\u00a0cell immunity","volume":"39","author":"Chow","year":"2021","journal-title":"Cancer Cell"},{"key":"2025100303494924000_10.12.e005345.19","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004001"},{"key":"2025100303494924000_10.12.e005345.20","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.07.050"},{"key":"2025100303494924000_10.12.e005345.21","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-570-1_4"},{"key":"2025100303494924000_10.12.e005345.22","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.137"},{"key":"2025100303494924000_10.12.e005345.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.053"},{"key":"2025100303494924000_10.12.e005345.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.04.003"},{"key":"2025100303494924000_10.12.e005345.25","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252"},{"key":"2025100303494924000_10.12.e005345.26","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy067"},{"key":"2025100303494924000_10.12.e005345.27","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2013.00281"},{"key":"2025100303494924000_10.12.e005345.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0399-6"},{"key":"2025100303494924000_10.12.e005345.29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1701219114"},{"key":"2025100303494924000_10.12.e005345.30","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4051"},{"key":"2025100303494924000_10.12.e005345.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.003"},{"key":"2025100303494924000_10.12.e005345.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001453"},{"key":"2025100303494924000_10.12.e005345.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2011.10.008"},{"key":"2025100303494924000_10.12.e005345.34","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3174"},{"key":"2025100303494924000_10.12.e005345.35","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The molecular signatures database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"2025100303494924000_10.12.e005345.36","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1038\/s41416-022-01742-5","article-title":"Peritoneal metastases from colorectal cancer belong to consensus molecular subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity","volume":"126","author":"Laoukili","year":"2022","journal-title":"Br J Cancer"},{"key":"2025100303494924000_10.12.e005345.37","doi-asserted-by":"publisher","DOI":"10.1038\/nature25492"},{"key":"2025100303494924000_10.12.e005345.38","doi-asserted-by":"publisher","DOI":"10.1038\/nature21349"},{"key":"2025100303494924000_10.12.e005345.39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI91190"},{"key":"2025100303494924000_10.12.e005345.40","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/s41423-020-0457-0","article-title":"Tertiary lymphoid structures in cancer - considerations for patient prognosis","volume":"17","author":"Munoz-Erazo","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"2025100303494924000_10.12.e005345.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0144-6"},{"key":"2025100303494924000_10.12.e005345.42","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1245\/s10434-020-09558-4","article-title":"Pressurized intraperitoneal aerosol chemotherapy (oxaliplatin) for unresectable colorectal peritoneal metastases: a multicenter, single-arm, phase II trial (CRC-PIPAC)","volume":"28","author":"Rovers","year":"2021","journal-title":"Ann Surg Oncol"},{"key":"2025100303494924000_10.12.e005345.43","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-88653-2","article-title":"Interleukin 10 level in the peritoneal cavity is a prognostic marker for peritoneal recurrence of T4 colorectal cancer","volume":"11","author":"Jeong","year":"2021","journal-title":"Sci Rep"},{"key":"2025100303494924000_10.12.e005345.44","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19991115)86:10<1936::AID-CNCR9>3.0.CO;2-9"},{"key":"2025100303494924000_10.12.e005345.45","doi-asserted-by":"publisher","DOI":"10.1006\/clim.2001.5163"},{"key":"2025100303494924000_10.12.e005345.46","doi-asserted-by":"publisher","DOI":"10.1309\/LM7T43AQZIUPIOWZ"},{"key":"2025100303494924000_10.12.e005345.47","doi-asserted-by":"publisher","DOI":"10.1002\/jso.20961"},{"key":"2025100303494924000_10.12.e005345.48","doi-asserted-by":"publisher","DOI":"10.3892\/ijo_00000767"},{"key":"2025100303494924000_10.12.e005345.49","doi-asserted-by":"crossref","first-page":"53","DOI":"10.29333\/ejgm\/82697","article-title":"Transforming growth factor beta-1 in human colorectal cancer patients","volume":"8","author":"\u00d6","year":"2011","journal-title":"Electronic Journal of General Medicine"},{"key":"2025100303494924000_10.12.e005345.50","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2018.11.043","article-title":"Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma","volume":"176","author":"Li","year":"2019","journal-title":"Cell"},{"key":"2025100303494924000_10.12.e005345.51","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"2025100303494924000_10.12.e005345.52","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24441"},{"key":"2025100303494924000_10.12.e005345.53","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2018.1513440","article-title":"A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy","volume":"8","author":"Varn","year":"2019","journal-title":"Oncoimmunology"},{"key":"2025100303494924000_10.12.e005345.54","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.cell.2019.10.028","article-title":"B cells and T follicular helper cells mediate response to checkpoint inhibitors in high mutation burden mouse models of breast cancer","volume":"179","author":"Hollern","year":"2019","journal-title":"Cell"},{"key":"2025100303494924000_10.12.e005345.55","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-6143.2001.10201.x"},{"key":"2025100303494924000_10.12.e005345.56","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41379-018-0113-8","article-title":"Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis","volume":"32","author":"Lee","year":"2019","journal-title":"Mod Pathol"},{"key":"2025100303494924000_10.12.e005345.57","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.cell.2019.10.029","article-title":"Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy","volume":"179","author":"Jiao","year":"2019","journal-title":"Cell"},{"key":"2025100303494924000_10.12.e005345.58","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3836"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-005345","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T10:50:02Z","timestamp":1759488602000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-005345"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12]]},"references-count":58,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,21]]},"published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1136\/jitc-2022-005345"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-005345","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12]]}}}