論文 - 詳細
| RRC ID | 89830 |
|---|---|
| 著者 | Ishihara H, Shibata H, Muraoka D, Demachi-Okamura A, Okamoto T, Mizuta R, Fukushima Y, Sugita Y, Ogasawara A, Nishida R, Beppu S, Terada H, Nishikawa D, Suzuki H, Masago K, Sasaki E, Sakakura N, Yamaguchi R, Hanai N, Ogawa T, Matsushita H. |
| タイトル | Characterization of persistent HPV-specific activated T cells in head and neck squamous cell carcinoma. |
| ジャーナル | Oncoimmunology |
| Abstract |
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. |
| 巻・号 | 15(1) |
| ページ | 2707808 |
| 公開日 | 2026-12-31 |
| DOI | 10.1080/2162402X.2026.2707808 |
| PMID | 42503644 |
| PMC | PMC13418702 |
| MeSH | Aged CD8-Positive T-Lymphocytes* / immunology Female Head and Neck Neoplasms* / immunology Head and Neck Neoplasms* / pathology Head and Neck Neoplasms* / virology Human papillomavirus 16* / immunology Humans Lymphocyte Activation / immunology Lymphocytes, Tumor-Infiltrating* / immunology Male Middle Aged NK Cell Lectin-Like Receptor Subfamily B / genetics NK Cell Lectin-Like Receptor Subfamily B / metabolism Oncogene Proteins, Viral / genetics Oncogene Proteins, Viral / immunology Papillomavirus E7 Proteins / genetics Papillomavirus E7 Proteins / immunology Papillomavirus Infections* / complications Papillomavirus Infections* / immunology Papillomavirus Infections* / virology Receptors, Antigen, T-Cell / genetics Receptors, Antigen, T-Cell / immunology Repressor Proteins / genetics Repressor Proteins / immunology Squamous Cell Carcinoma of Head and Neck* / immunology Squamous Cell Carcinoma of Head and Neck* / virology T-Cell Exhaustion |
| リソース情報 | |
| 遺伝子材料 | Human HLA-B*52:01:01 cDNA (RDB02882) Human HLA-C*12:02:02 cDNA (RDB02889) Human HLA-C*14:02:01 cDNA (RDB03378) |