{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:21:35Z","timestamp":1793744495534,"version":"4.6.1"},"posted":{"date-parts":[[2026,9,16]]},"group-title":"Immunology","reference-count":79,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NIH NIAID","award":["DP2AI171161"],"award-info":[{"award-number":["DP2AI171161"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Blockade of inhibitory PD-1 signaling on T cells is a cornerstone of cancer immunotherapy, with current strategies targeting PD-1 or its ligand PD-L1. However, PD-1 engages an alternative ligand, PD-L2, whose role in tumor immunity remains poorly defined. Here, we show that PD-L2 is upregulated on intratumoral CCR7\u207a conventional dendritic cells (cDCs) in both mouse and human melanoma. Using genetic mouse models enabling selective ablation of PD-L1 or PD-L2 in cDCs, we identify a division of labor between these ligands: PD-L1 controls the size of the progenitor CD8\u207a T cell pool in tumor-draining lymph nodes by modulating stem-like CD8\u207a T cells, whereas PD-L2 limits progenitor exhausted CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell differentiation within the tumor microenvironment. Loss of PD-L2 in cDCs enhances cytotoxic CD8\u207a T cell responses and suppresses tumor growth, particularly in tumors enriched for CCR7\u207a cDC1s. Consistent with this, increased CCR7\n                  <jats:sup>+<\/jats:sup>\n                  cDC abundance is associated with poor prognosis in human cancers. Spatial transcriptomic analyses reveal co-localization of CCR7\u207a cDC1s and Tpex within CCL19\n                  <jats:sup>hi<\/jats:sup>\n                  niches, where cancer-associated fibroblasts serve as the predominant source of CCL19. Finally, intratumoral GM-CSF drives PD-L2 expression on CCR7\u207a cDCs, with Tpex and NK cells as major sources. Together, these findings establish cDC\u2013 associated PD-L1 and PD-L2 as spatially and functionally distinct checkpoints governing CD8\u207a T cell differentiation. Our results suggest that the abundance of CCR7\u207aPD-L2\u207a cDC1s may guide the choice between anti\u2013PD-1 and anti\u2013 PD-L1 therapies and support the development of PD-L2\u2013directed blockade.\n                <\/jats:p>","DOI":"10.64898\/2026.09.10.750646","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:10:16Z","timestamp":1789564216000},"source":"Crossref","is-referenced-by-count":1,"title":["Dendritic cell PD-L2 restrains intratumoral CD8\n                  <sup>+<\/sup>\n                  T cell immunity"],"prefix":"10.64898","author":[{"given":"Jinwoo","family":"Nah","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Sun","sequence":"additional","affiliation":[{"name":"Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anushka","family":"Yadav","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina","family":"Scheinfeld","sequence":"additional","affiliation":[{"name":"Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamjeed","family":"Azad","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Princeton University, Princeton, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Rose","sequence":"additional","affiliation":[{"name":"Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1541-7867","authenticated-orcid":false,"given":"Burkhard","family":"Becher","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Smithy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Postow","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, USA"},{"name":"Weill Cornell Medical College, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte E.","family":"Ariyan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Memorial Sloan Kettering Cancer Center, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6589-981X","authenticated-orcid":false,"given":"Yuri","family":"Pritykin","sequence":"additional","affiliation":[{"name":"Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA"},{"name":"Department of Computer Science, Princeton University, Princeton, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5834-926X","authenticated-orcid":false,"given":"Chrysothemis C.","family":"Brown","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA"},{"name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 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