{
  "abstract": "Tumor-infiltrating CD8+ T cells are transcriptionally heterogeneous, and robust features linking their clonal dynamics to experimentally defined tumor reactivity remain incompletely characterized. We integrated single-cell RNA sequencing (scRNA-seq) and paired T-cell receptor sequencing (scTCR-seq) data from 31 single-cell immune datasets to characterize CD8+ T-cell states associated with clonal expansion and tumor reactivity. Across cancers, HLA-II-expressing CD8+ T cells were enriched in activated, cytotoxic, proliferative, exhausted, and terminally differentiated states and were preferentially associated with expanded TCR clonotypes. Pseudotime analysis indicated that HLA-II expression occurs along late differentiation states. HLA-DR blockade reduced CD25 upregulation in activated mixed PBMC and purified CD8+ T-cell cultures and attenuated CellTrace CFSE dilution in purified CD8+ T cells. An HLA-II-associated CD8+ T-cell signature showed cancer-type-dependent survival associations, including longer overall survival in several cohorts. To evaluate its contribution to tumor-reactivity prediction, an expansion-pretrained DNN was adapted using experimentally annotated tumor-reactive and non-tumor-reactive clonotypes from six pancreatic ductal adenocarcinoma samples and evaluated in 2225 functionally annotated CD8+ T cells from three held-out samples. Adding six HLA-II genes improved ROC-AUC across three feature panels from 0.540 to 0.781, 0.626 to 0.732, and 0.838 to 0.878, respectively, and improved PR-AUC from 0.570 to 0.739, 0.640 to 0.718, and 0.799 to 0.869. These findings identify HLA-II expression as a feature of activated and clonally expanded CD8+ T-cell states and support the complementary value of HLA-II-associated transcriptional features for prioritizing candidate tumor-reactive TCRs.",
  "abstract_shown": true,
  "affiliations": [
    "State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China",
    "Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Baiziting 42, Nanjing, 210009, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xue Mi"
    },
    {
      "affs": [
        1
      ],
      "name": "Jinghua Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhu Dai"
    },
    {
      "affs": [
        0
      ],
      "name": "Ruyue Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Dongmei Tian"
    },
    {
      "affs": [
        1
      ],
      "name": "Guochun Cao"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhongdang Xiao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/11fc4sfajt8ne.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27188338",
  "fulltext_url": null,
  "id": "11fc4sfajt8ne",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/18/8338",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7214434286",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-19",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/11fc4sfajt8ne.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:55Z",
      "native_id": "10.3390/ijms27188338",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/18/8338"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "HLA-II Expression Marks Activated and Clonally Expanded CD8+ T Cells and Improves Tumor-Reactivity Prediction Across Human Cancers",
  "title_text": "HLA-II Expression Marks Activated and Clonally Expanded CD8+ T Cells and Improves Tumor-Reactivity Prediction Across Human Cancers",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:55Z",
  "url": "https://research.draconitic.com/paper/11fc4sfajt8ne",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}