{
  "abstract": "Background: Immune checkpoint inhibitors (ICI) are efficacious in many solid tumors, but response in glioma is restricted to a small subgroup. The determinants of response and resistance to ICI remain poorly understood. Methods: Here we exploit a syngeneic hypermutated high-grade glioma model with dichotomous response to combined PD-1 and CTLA-4 inhibition to unravel determinants of tumor-infiltrating T-cells driving response. Tumor-infiltrating T-cells from ICI-responsive and non-responsive tumors were analyzed by single-cell RNA and T-cell receptor sequencing and tumor-reactive T-cell receptor clonotypes were functionally validated to characterize their transcriptional phenotypes. We verify our findings in IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab. Results: ICI response was associated with intratumoral clonal expansion of tumor-reactive cytotoxic T-cells and increased infiltration of CXCR6+ CD4+ tissue resident memory T-cells (Trm). CD4 stem-like memory T-cells in responding tumors demonstrated elevated interferon responses, following trajectories toward clonally expanded Trm, versus trajectories toward exhaustion in non-responsive tumors. In responsive tumors, CD4+ Trm interacted with infiltrating CXCR3+ tumor-reactive and clonally expanded, yet transcriptionally versatile cytotoxic T-cells. Probing the post neoadjuvant ICI high-grade glioma patient tissue dataset, we confirmed increased CXCR6 expression in CD4+ T cells and the association of CD4+ Trm with prolonged overall survival. Conclusion: These findings identify CD4 tissue-resident memory T-cells as determinants of ICI response in IDH1 wildtype high-grade glioma and warrant their further investigation to improve immunotherapy outcomes.",
  "abstract_shown": true,
  "affiliations": [
    "German Cancer Research Center Heidelberg"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "V. Turco"
    },
    {
      "name": "C. L. Tan"
    },
    {
      "name": "D. A. Agardy"
    },
    {
      "name": "K. Lindner"
    },
    {
      "name": "G. Herrera"
    },
    {
      "name": "L. Sun"
    },
    {
      "name": "J. Rosenbauer"
    },
    {
      "name": "B. Zhao"
    },
    {
      "name": "M. O. Breckwoldt"
    },
    {
      "affs": [
        0
      ],
      "name": "L. Bunse"
    },
    {
      "name": "R. Prins"
    },
    {
      "name": "E. W. Green"
    },
    {
      "name": "M. Platten"
    },
    {
      "affs": [
        0
      ],
      "name": "T. Bunse"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/71n872vzt7zce.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.28.754895",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1.full",
  "id": "71n872vzt7zce",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7214777255",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/71n872vzt7zce.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:06Z",
      "native_id": "10.64898/2026.09.28.754895",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma",
  "title_text": "Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:06Z",
  "url": "https://research.draconitic.com/paper/71n872vzt7zce",
  "venue": "bioRxiv",
  "versions": []
}