---
title: "CD8+ tumor-infiltrating lymphocytes in glioblastoma show distinct exhaustion signatures and potent"
id: "british-journal-of-cancer-0-abundant-cd8-tumor-infiltrating-lymphocytes-in-glioblastoma-harbor-distinct"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-abundant-cd8-tumor-infiltrating-lymphocytes-in-glioblastoma-harbor-distinct"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03619-3"
published_at: "2026-10-05T12:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CD8+ tumor-infiltrating lymphocytes in glioblastoma show distinct exhaustion signatures and potent
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-abundant-cd8-tumor-infiltrating-lymphocytes-in-glioblastoma-harbor-distinct
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03619-3)
- **Published At:** 2026-10-05T12:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study examined intratumoral T cells in newly diagnosed IDH-wildtype **glioblastoma** to identify tumor-specific T cells as a basis for antigen-targeted immunotherapy. - Tumor specimens from 56 patients were screened; cases with prominent intratumoral T-cell infiltration were selected for deeper analysis. - In TIL-rich tumors, CD3+CD8+CD4- T cells were sorted and subjected to single-cell RNA sequencing and T-cell receptor (TCR) sequencing to resolve transcriptional states and clonality. - Integrated analyses combined the authors' single-cell dataset (ACC) with publicly available GBM TIL datasets (PA) and lung cancer TIL/malignant pleural effusion datasets (LC). - Unsupervised analysis identified a dominant T-cell cluster marked by high expression of exhaustion markers, notably **LAG3**, and high **TCR clonality**, suggesting clonal expansion within exhausted populations. - Expression of **LAG3** and **CXCL13** was significantly higher in the ACC TIL-rich subset compared with the PA dataset, indicating distinct exhaustion-related transcriptional features in some GBM cases. - An AI-based prediction algorithm estimated that the ACC TIL-rich subset contained a markedly higher proportion of potentially **tumor-reactive** T cells than the PA and LC datasets. - The authors propose that clonally expanded, exhausted **CD8+ TILs** in certain GBM cases may include potentially reactive cells and could be targets for antigen-specific and **LAG-3**-targeted immunotherapies. - Figures illustrate identification of TIL-rich GBM cases, single-cell analyses, integrated dataset comparisons, associations between clonality and transcriptional profiles, and distribution of predicted tumor-reactive T cells across datasets. - Datasets and custom R scripts used in analyses are available from the corresponding authors upon reasonable request; software packages and versions are described in Materials and Methods.
## Clinical Analysis & Structured Key Points
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[articles](https://www.nature.com/bjc/articles?type=article) 4. article * Article * Published: 05 October 2026 Cellular and Molecular Biology # Abundant CD8+ tumor-infiltrating lymphocytes in glioblastoma harbor distinct exhaustion signatures in potentially reactive subsets * [Takanari Okamoto](https://www.nature.com/articles/s41416-026-03619-3#auth-Takanari-Okamoto-Aff1-Aff2) [ORCID: orcid.org/0000-0002-4124-180X](https://orcid.org/0000-0002-4124-180X)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1),[2](https://www.nature.com/articles/s41416-026-03619-3#Aff2), * [Ryo Mizuta](https://www.nature.com/articles/s41416-026-03619-3#auth-Ryo-Mizuta-Aff1-Aff3)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1),[3](https://www.nature.com/articles/s41416-026-03619-3#Aff3), * [Ayako Demachi-Okamura](https://www.nature.com/articles/s41416-026-03619-3#auth-Ayako-Demachi_Okamura-Aff1)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1), * [Daisuke Muraoka](https://www.nature.com/articles/s41416-026-03619-3#auth-Daisuke-Muraoka-Aff1-Aff4)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1),[4](https://www.nature.com/articles/s41416-026-03619-3#Aff4), * [Yasunori Fukushima](https://www.nature.com/articles/s41416-026-03619-3#auth-Yasunori-Fukushima-Aff1)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1), * [Hiromasa Ishihara](https://www.nature.com/articles/s41416-026-03619-3#auth-Hiromasa-Ishihara-Aff1)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1), * [Yujia Sun](https://www.nature.com/articles/s41416-026-03619-3#auth-Yujia-Sun-Aff1)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1), * [Yizheng Wang](https://www.nature.com/articles/s41416-026-03619-3#auth-Yizheng-Wang-Aff1)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1), * [Reina Nishida](https://www.nature.com/articles/s41416-026-03619-3#auth-Reina-Nishida-Aff1)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1), * [Eiichi Sasaki](https://www.nature.com/articles/s41416-026-03619-3#auth-Eiichi-Sasaki-Aff5)[5](https://www.nature.com/articles/s41416-026-03619-3#Aff5), * [Katsuhiro Masago](https://www.nature.com/articles/s41416-026-03619-3#auth-Katsuhiro-Masago-Aff5)[5](https://www.nature.com/articles/s41416-026-03619-3#Aff5), * [Kazuhide Onoguchi](https://www.nature.com/articles/s41416-026-03619-3#auth-Kazuhide-Onoguchi-Aff6)[6](https://www.nature.com/articles/s41416-026-03619-3#Aff6), * [Yuki Tanaka](https://www.nature.com/articles/s41416-026-03619-3#auth-Yuki-Tanaka-Aff6)[6](https://www.nature.com/articles/s41416-026-03619-3#Aff6), * [Yoshiko Yamashita](https://www.nature.com/articles/s41416-026-03619-3#auth-Yoshiko-Yamashita-Aff6)[6](https://www.nature.com/articles/s41416-026-03619-3#Aff6), * [Richard Stratford](https://www.nature.com/articles/s41416-026-03619-3#auth-Richard-Stratford-Aff7)[7](https://www.nature.com/articles/s41416-026-03619-3#Aff7), * [Trevor Clancy](https://www.nature.com/articles/s41416-026-03619-3#auth-Trevor-Clancy-Aff7)[7](https://www.nature.com/articles/s41416-026-03619-3#Aff7), * [Osamu Muto](https://www.nature.com/articles/s41416-026-03619-3#auth-Osamu-Muto-Aff8-Aff9)[8](https://www.nature.com/articles/s41416-026-03619-3#Aff8),[9](https://www.nature.com/articles/s41416-026-03619-3#Aff9), * [Chin Leng Tan](https://www.nature.com/articles/s41416-026-03619-3#auth-Chin_Leng-Tan-Aff10-Aff11-Aff12-Aff13) [ORCID: orcid.org/0000-0002-2529-1030](https://orcid.org/0000-0002-2529-1030)[10](https://www.nature.com/articles/s41416-026-03619-3#Aff10),[11](https://www.nature.com/articles/s41416-026-03619-3#Aff11),[12](https://www.nature.com/articles/s41416-026-03619-3#Aff12),[13](https://www.nature.com/articles/s41416-026-03619-3#Aff13), * [Yoshihiro Otani](https://www.nature.com/articles/s41416-026-03619-3#auth-Yoshihiro-Otani-Aff3)[3](https://www.nature.com/articles/s41416-026-03619-3#Aff3), * [Yoshinobu Takahashi](https://www.nature.com/articles/s41416-026-03619-3#auth-Yoshinobu-Takahashi-Aff2)[2](https://www.nature.com/articles/s41416-026-03619-3#Aff2), * [Rui Yamaguchi](https://www.nature.com/articles/s41416-026-03619-3#auth-Rui-Yamaguchi-Aff8-Aff9)[8](https://www.nature.com/articles/s41416-026-03619-3#Aff8),[9](https://www.nature.com/articles/s41416-026-03619-3#Aff9), * [Edward W. Green](https://www.nature.com/articles/s41416-026-03619-3#auth-Edward_W_-Green-Aff10-Aff11-Aff12)[10](https://www.nature.com/articles/s41416-026-03619-3#Aff10),[11](https://www.nature.com/articles/s41416-026-03619-3#Aff11),[12](https://www.nature.com/articles/s41416-026-03619-3#Aff12), * [Michael Platten](https://www.nature.com/articles/s41416-026-03619-3#auth-Michael-Platten-Aff10-Aff11-Aff12-Aff13-Aff14)[10](https://www.nature.com/articles/s41416-026-03619-3#Aff10),[11](https://www.nature.com/articles/s41416-026-03619-3#Aff11),[12](https://www.nature.com/articles/s41416-026-03619-3#Aff12),[13](https://www.nature.com/articles/s41416-026-03619-3#Aff13),[14](https://www.nature.com/articles/s41416-026-03619-3#Aff14), * [Isao Date](https://www.nature.com/articles/s41416-026-03619-3#auth-Isao-Date-Aff3)[3](https://www.nature.com/articles/s41416-026-03619-3#Aff3), * [Shota Tanaka](https://www.nature.com/articles/s41416-026-03619-3#auth-Shota-Tanaka-Aff3)[3](https://www.nature.com/articles/s41416-026-03619-3#Aff3), * [Naoya Hashimoto](https://www.nature.com/articles/s41416-026-03619-3#auth-Naoya-Hashimoto-Aff2)[2](https://www.nature.com/articles/s41416-026-03619-3#Aff2) & * … * [Hirokazu Matsushita](https://www.nature.com/articles/s41416-026-03619-3#auth-Hirokazu-Matsushita-Aff1) [ORCID: orcid.org/0000-0001-9069-7160](https://orcid.org/0000-0001-9069-7160)[1](https://www.nature.com/articles/s41416-026-03619-3#Aff1) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03619-3#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03619-3/save-research?_csrf=sZz76XcVk-ETExMl3IGgmMmWDcvacBpU) [ View saved research ](https://www.nature.com/saved-research) ## Abstract ### Background The effectiveness of immunotherapy against glioblastoma (GBM) remains limited, suggesting that antigen-specific tumor-infiltrating lymphocytes (TILs) are rare. This study aimed to identify tumor-specific T cells in GBM as the basis for antigen-specific immunotherapy. ### Methods Tumor specimens were collected from 56 patients newly diagnosed with IDH-wildtype GBM. In cases showing prominent intratumoral T-cell infiltration, CD3⁺CD8⁺CD4⁻ T cells were sorted for single-cell RNA and T-cell receptor (TCR) sequencing. Integrated analyses were performed using our single-cell dataset from the Aichi Cancer Center (ACC), publicly available GBM TILs datasets (PA), and lung cancer TILs and malignant pleural effusions datasets (LC). Candidate reactive TCRs were identified using an AI-based algorithm. ### Results Unsupervised analysis identified a dominant cluster characterized by the strong expression of exhaustion markers, most prominently _LAG3_ , with high TCR clonality. Moreover, _LAG3_ and _CXCL13_ expression levels were significantly higher in the ACC TIL-rich subset than the PA dataset. Finally, a prediction algorithm suggested that our TIL-rich subset harbored a markedly higher proportion of potentially reactive T cells than the PA and LC datasets. ### Conclusions TILs with marked clonal expansion in certain GBM cases may include potentially reactive T cells with distinct exhaustion features, providing a foundation for the development of antigen-specific and LAG-3-targeted immunotherapies. This is a preview of subscription content, [access via your institution](https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41416-026-03619-3) ## Access options [ Access through your institution ](https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41416-026-03619-3) Subscribe to this journal Receive 24 print issues and online access 251,40 € per year only 10,48 € per issue [Learn more](https://www.nature.com/bjc/subscribe) Buy this article * Purchase on SpringerLink * Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout ### Additional access options: * [Log in](https://idp.nature.com/auth/personal/springernature?client_id=grover&redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41416-026-03619-3) * [Learn about institutional subscriptions](https://www.springernature.com/gp/librarians/licensing/license-options) * [Read our FAQs](https://support.nature.com/en/support/home) * [Contact customer support](https://www.springernature.com/gp/contact) **Fig. 1: Identification of GBM cases with abundant TILs.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41416-026-03619-3/MediaObjects/41416_2026_3619_Fig1_HTML.png) **Fig. 2: Single-cell analysis of CD8 + TILs from two TIL-rich GBM cases.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41416-026-03619-3/MediaObjects/41416_2026_3619_Fig2_HTML.png) **Fig. 3: Integrated single-cell analysis of CD8 + TILs from ACC-2S and PA datasets.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41416-026-03619-3/MediaObjects/41416_2026_3619_Fig3_HTML.png) **Fig. 4: Association between TCR clonality and transcriptional profiles of GBM-infiltrating T cells.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41416-026-03619-3/MediaObjects/41416_2026_3619_Fig4_HTML.png) **Fig. 5: Integrated analysis of GBM TILs from the ACC-2S dataset and LC samples.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41416-026-03619-3/MediaObjects/41416_2026_3619_Fig5_HTML.png) **Fig. 6: Distribution of predicted tumor-reactive T cells across GBM and LC datasets.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41416-026-03619-3/MediaObjects/41416_2026_3619_Fig6_HTML.png) ### Explore related subjects Discover the latest articles and news in related subjects. * [CNS cancer](https://www.nature.com/subjects/cns-cancer) * [Cytotoxic T cells](https://www.nature.com/subjects/cytotoxic-t-cells) * [Immunoediting](https://www.nature.com/subjects/immunoediting) ## Data availability The datasets generated and/or analyzed during the current study are available from the corresponding authors upon reasonable request. ## Code availability Custom R scripts used for statistical analyses, data visualization, and generation of key figures are available from the corresponding authors upon reasonable request. 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