{
  "abstract": "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+ 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 T cell pool in tumor-draining lymph nodes by modulating stem-like CD8 T cells, whereas PD-L2 limits progenitor exhausted CD8 T cell differentiation within the tumor microenvironment. Loss of PD-L2 in cDCs enhances cytotoxic CD8 T cell responses and suppresses tumor growth, particularly in tumors enriched for CCR7+ cDC1s. Consistent with this, increased CCR7+ cDC abundance is associated with poor prognosis in human cancers. Spatial transcriptomic analyses reveal co-localization of CCR7+ cDC1s and Tpex within CCL19hi niches, where cancer-associated fibroblasts serve as the predominant source of CCL19. Finally, intratumoral GM-CSF drives PD-L2 expression on CCR7+ cDCs, with Tpex and NK cells as major sources. Together, these findings establish cDC-associated PD-L1 and PD-L2 as spatially and functionally distinct checkpoints governing CD8 T cell differentiation. Our results suggest that the abundance of CCR7+ cDC1s may guide the choice between anti-PD-1 and anti-PD-L1 therapies and support the development of PD-L2-directed blockade.",
  "abstract_shown": true,
  "affiliations": [
    "Memorial Sloan Kettering Cancer Center"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "J. Nah"
    },
    {
      "name": "A. Sun"
    },
    {
      "name": "A. Yadav"
    },
    {
      "name": "A. Scheinfeld"
    },
    {
      "name": "T. Azad"
    },
    {
      "name": "S. Rose"
    },
    {
      "name": "B. Becher"
    },
    {
      "name": "J. W. Smithy"
    },
    {
      "name": "M. A. Postow"
    },
    {
      "name": "C. E. Ariyan"
    },
    {
      "name": "Y. Pritykin"
    },
    {
      "affs": [
        0
      ],
      "name": "C. Brown"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ad4p1xtshhe3t.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.10.750646",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750646v1.full",
  "id": "ad4p1xtshhe3t",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750646v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7213265166",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750646v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ad4p1xtshhe3t.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:38Z",
      "native_id": "10.64898/2026.09.10.750646",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750646v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Dendritic cell PD-L2 restrains intratumoral CD8+ T cell immunity",
  "title_text": "Dendritic cell PD-L2 restrains intratumoral CD8+ T cell immunity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:38Z",
  "url": "https://research.draconitic.com/paper/ad4p1xtshhe3t",
  "venue": "bioRxiv",
  "versions": []
}