Oncoimmunology · 2026
Characterization of persistent HPV-specific activated T cells in head and neck squamous cell carcinoma.
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Ishihara Hiromasa, Shibata Hirofumi, Muraoka Daisuke, Demachi-Okamura Ayako, Okamoto Takanari, Mizuta Ryo, Fukushima Yasunori, Sugita Yusuke, Ogasawara Aiko, Nishida Reina, Beppu Shintaro, Terada Hoshino, Nishikawa Daisuke, Suzuki Hidenori, Masago Katsuhiro, Sasaki Eiichi, Sakakura Noriaki, Yamaguchi Rui, Hanai Nobuhiro, Ogawa Takenori, Matsushita Hirokazu
Аннотация
BACKGROUND: Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) generally has favorable outcomes yet remains prone to late recurrence. Durable control likely depends on persistent tumor-specific CD8+ T cells, but their persistence and function in metastasis are poorly understood.
METHODS: We integrated bulk RNA sequencing (n = 56) with single-cell RNA and paired T-cell receptor (TCR) sequencing of tumor-infiltrating CD8+ T cells (n = 4), including a longitudinal primary-lung metastasis pair obtained three years after curative therapy. HPV genotyping, HLA typing, epitope prediction, and NFAT-reporter Jurkat-luciferase assays were used to identify and functionally validate HPV16 E6/E7-specific TCRs. Repertoire tracking and single-cell/bulk transcriptomics were evaluated.
RESULTS: HPV + tumors showed higher inferred CD8+ T cell infiltration and more favorable prognosis than HPV- tumors. Single-cell analysis revealed oligoclonally expanded exhausted clusters enriched in HPV tumor-specific CD8+ T cells. We isolated and functionally validated nine patient-derived HPV16 E6/E7-specific TCRs. High-avidity receptors recognizing an alternatively spliced region in E6 (aa 49-110; E6*) persisted in metastatic lesions, whereas lower-avidity clones, including an E7_11-19-specific TCR currently under clinical investigation, were lost. Compared with the primary tumor, metastatic lesions showed reduced stem-like/TCF7-associated CD8+ T-cell populations and enrichment of HPV-specific CD8+ T cells expressing KLRB1 and ZNF683, consistent with a tissue-adapted TRM-like transcriptional state with inhibitory signaling features.
CONCLUSIONS: High-avidity, KLRB1 + HPV-specific CD8+ T cells represent a persistent effector subset with prognostic and therapeutic relevance to HPV + OPSCC. Their persistence in metastatic lesions and association with reduced recurrence risk support further investigation of KLRB1-associated HPV-reactive T-cell states as biomarkers and immunotherapeutic targets.
METHODS: We integrated bulk RNA sequencing (n = 56) with single-cell RNA and paired T-cell receptor (TCR) sequencing of tumor-infiltrating CD8+ T cells (n = 4), including a longitudinal primary-lung metastasis pair obtained three years after curative therapy. HPV genotyping, HLA typing, epitope prediction, and NFAT-reporter Jurkat-luciferase assays were used to identify and functionally validate HPV16 E6/E7-specific TCRs. Repertoire tracking and single-cell/bulk transcriptomics were evaluated.
RESULTS: HPV + tumors showed higher inferred CD8+ T cell infiltration and more favorable prognosis than HPV- tumors. Single-cell analysis revealed oligoclonally expanded exhausted clusters enriched in HPV tumor-specific CD8+ T cells. We isolated and functionally validated nine patient-derived HPV16 E6/E7-specific TCRs. High-avidity receptors recognizing an alternatively spliced region in E6 (aa 49-110; E6*) persisted in metastatic lesions, whereas lower-avidity clones, including an E7_11-19-specific TCR currently under clinical investigation, were lost. Compared with the primary tumor, metastatic lesions showed reduced stem-like/TCF7-associated CD8+ T-cell populations and enrichment of HPV-specific CD8+ T cells expressing KLRB1 and ZNF683, consistent with a tissue-adapted TRM-like transcriptional state with inhibitory signaling features.
CONCLUSIONS: High-avidity, KLRB1 + HPV-specific CD8+ T cells represent a persistent effector subset with prognostic and therapeutic relevance to HPV + OPSCC. Their persistence in metastatic lesions and association with reduced recurrence risk support further investigation of KLRB1-associated HPV-reactive T-cell states as biomarkers and immunotherapeutic targets.
Предметные рубрики MeSH
HumansCD8-Positive T-LymphocytesPapillomavirus InfectionsRepressor ProteinsFemaleLymphocytes, Tumor-InfiltratingSquamous Cell Carcinoma of Head and NeckOncogene Proteins, ViralMaleReceptors, Antigen, T-CellLymphocyte ActivationPapillomavirus E7 ProteinsNK Cell Lectin-Like Receptor Subfamily BMiddle AgedT-Cell ExhaustionHuman papillomavirus 16Head and Neck NeoplasmsAged