---
title: "CD4+ Tissue-Resident Memory T Cells Predict Checkpoint Inhibitor Response in High-Grade Glioma"
id: "biorxiv-1-tissue-resident-cd4-memory-t-cells-mark-response-to-immune-checkpoint"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-1-tissue-resident-cd4-memory-t-cells-mark-response-to-immune-checkpoint"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1?rss=1"
published_at: "2026-09-29T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CD4+ Tissue-Resident Memory T Cells Predict Checkpoint Inhibitor Response in High-Grade Glioma
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-1-tissue-resident-cd4-memory-t-cells-mark-response-to-immune-checkpoint
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1?rss=1)
- **Published At:** 2026-09-29T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- This preprint used a syngeneic hypermutated high-grade glioma model showing a dichotomous outcome to combined **PD-1** and **CTLA-4** blockade to identify intratumoral T-cell features that associate with response. - Tumor-infiltrating T cells from responding and non-responding tumors were profiled by single-cell RNA sequencing and T-cell receptor (TCR) sequencing to map transcriptional phenotypes and clonal expansion. - Response to immune checkpoint inhibition (ICI) correlated with intratumoral clonal expansion of tumor-reactive cytotoxic T cells and increased infiltration of **CXCR6+ CD4+ tissue-resident memory (Trm)** T cells. - In responding tumors, CD4+ stem-like memory T cells exhibited elevated interferon response programs and developmental trajectories toward clonally expanded Trm, whereas in non-responding tumors trajectories favored exhaustion. - CD4+ Trm in responsive tumors engaged with infiltrating CXCR3+ tumor-reactive and clonally expanded cytotoxic T cells that retained transcriptional versatility. - Findings from the mouse model were validated in IDH1 wildtype high-grade glioblastoma patient tissue after neoadjuvant **pembrolizumab**, showing increased **CXCR6** expression in CD4+ T cells and an association of CD4+ Trm with prolonged overall survival. - The authors conclude that **CD4+ tissue-resident memory T cells** are determinants of ICI response in IDH1 wildtype high-grade glioma and propose further investigation to improve immunotherapy outcomes. - The article is a preprint and has not undergone peer review; competing interests and funders are declared in the source.
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Verena Turco 1 German Cancer Research Center Heidelberg; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Verena%2BTurco%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Turco%20V&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AVerena%2BTurco%2B) Chin Leng Tan 1 German Cancer Research Center Heidelberg; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Chin%2BLeng%2BTan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Tan%20CL&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AChin%2BLeng%2BTan%2B) Dennis Alexander Agardy 1 German Cancer Research Center Heidelberg; 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* [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Theresa%2BBunse%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Bunse%20T&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATheresa%2BBunse%2B) * For correspondence: t.bunse@dkfz.de * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5821812/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5821812/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5821812/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5821812/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.28.754895v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5821812/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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. ### Competing Interest Statement M.P. is founder of Tcelltech GmbH. L.B. and M.P. have patents on glioblastoma-specific T cell receptors and AI-guided prediction of brain-tumor reactive T cell receptors ## Funder Information Declared German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), 404521405, 259332240 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC 4.0 International license](http://creativecommons.org/licenses/by-nc/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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