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Papillomavirus Infections / Head and Neck Neoplasms / T-cell Receptor Sequencing · Journal article
Oncoimmunology · July 26, 2026
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This mechanistic study integrates single-cell and bulk transcriptomics to characterize HPV-specific CD8+ T-cell populations in HPV+ oropharyngeal cancer, with functional validation of nine patient-derived TCRs. High-avidity TCRs recognizing alternatively spliced E6 persist in metastatic lesions and are associated with a tissue-resident memory-like phenotype, suggesting prognostic relevance, but clinical outcome associations are descriptive rather than quantified.
Integrated bulk RNA sequencing with single-cell RNA and paired T-cell receptor sequencing. Patients with HPV+ oropharyngeal squamous cell carcinoma; single-cell cohort comprised 4 patients with available tumor tissue.. Intervention: Single-cell RNA and TCR sequencing of tumor-infiltrating CD8+ T cells with functional TCR validation by NFAT-reporter assays. Compared with: HPV- tumors (inferred CD8+ infiltration and prognosis compared); primary vs. metastatic lesion phenotypes compared within one longitudinal case. n = 4.
Nine patient-derived HPV16 E6/E7-specific TCRs were isolated and functionally validated by NFAT-reporter assays High-avidity receptors recognizing E6* (aa 49-110) persisted in metastatic lesions three years after curative therapy Lower-avidity clones, including E7_11-19-specific TCR under clinical investigation, were lost in metastatic lesions
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Identification of high-avidity, KLRB1+ HPV-specific CD8+ T cells as persistent effector subsets may inform future biomarker development and immunotherapeutic strategies in HPV+ OPSCC. The persistence of specific TCRs in metastatic disease over three years suggests mechanistic relevance to long-term disease control, warranting larger cohort validation.
Single-center mechanistic study with small sample size (n=4 for single-cell analysis) characterizing HPV-specific T-cell populations; functional validation of TCRs supports hypothesis but lacks clinical endpoint data or comparative outcome analysis.
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Identification of high-avidity, KLRB1+ HPV-specific CD8+ T cells as persistent effector subsets may inform future biomarker development and immunotherapeutic strategies in HPV+ OPSCC. The persistence of specific TCRs in metastatic disease over three years suggests mechanistic relevance to long-term disease control, warranting larger cohort validation.
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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.
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