British journal of cancer · 2026
Abundant CD8+ tumor-infiltrating lymphocytes in glioblastoma harbor distinct exhaustion signatures in potentially reactive subsets.
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Okamoto Takanari, Mizuta Ryo, Demachi-Okamura Ayako, Muraoka Daisuke, Fukushima Yasunori, Ishihara Hiromasa, Sun Yujia, Wang Yizheng, Nishida Reina, Sasaki Eiichi, Masago Katsuhiro, Onoguchi Kazuhide, Tanaka Yuki, Yamashita Yoshiko, Stratford Richard, Clancy Trevor, Muto Osamu, Tan Chin Leng, Otani Yoshihiro, Takahashi Yoshinobu, Yamaguchi Rui, Green Edward W, Platten Michael, Date Isao, Tanaka Shota, Hashimoto Naoya, Matsushita Hirokazu
Аннотация
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.
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.