Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan;
Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.
Anticancer Res. 2024 Jul;44(7):2921-2931. doi: 10.21873/anticanres.17104.
BACKGROUND/AIM: Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is clinically and immunologically distinct from HPV-negative HNSCC. Herein, we investigated the presence of tumor antigens HPV E6/E7 and wild-type p53-specific T-cell responses, and the impact of immune checkpoint blockade in patients with HPV-positive HNSCC.
Peripheral blood mononuclear cells (PBMCs) from patients with HPV-positive HNSCC were stimulated with HPV E6/E7 or wild-type p53-derived peptide mixture and evaluated using the interferon-γ enzyme-linked immunosorbent spot assay. Flow cytometry was performed to analyze the proportion of T-cell subsets and T cells expressing immune checkpoint molecules.
HPV E6/E7-specific T cells were detected in 22 (95.7%) of 23 patients, whereas wild-type p53-specific T cells were detected in 3 (15.0%) of 20 patients. Seven (43.8%) of 16 patients exhibited wild-type p53-specific T-cell responses, as determined using whole proteins instead of peptides. Immune checkpoint blockade enhanced wild-type p53-specific T-cell responses in 9 (45.0%) of 20 patients. Flow cytometric analysis of PBMCs revealed that responders exhibiting enhanced wild-type p53-specific T-cell responses following immune checkpoint blockade had a significantly higher proportion of Ki-67+CD4+ T cells, Ki-67+CD8+ T cells, regulatory T cells, PD-1+CD4+ T cells, and TIM-3+CD4+ T cells than non-responders.
Our findings indicate that tumor antigen-specific T cells are present in the peripheral blood of patients with HPV-positive HNSCC. Blockade of checkpoint pathways can enhance T-cell responses in certain patients, probably via activated T cells, Tregs, and/or exhausted CD4+ T cells.
背景/目的：人乳头瘤病毒（HPV）阳性头颈部鳞状细胞癌（HNSCC）在临床和免疫方面有别于 HPV 阴性 HNSCC。在此，我们研究了 HPV 阳性 HNSCC 患者中肿瘤抗原 HPV E6/E7 和野生型 p53 特异性 T 细胞反应的存在情况，以及免疫检查点阻断的影响。
从 HPV 阳性 HNSCC 患者的外周血单核细胞（PBMC）中刺激 HPV E6/E7 或野生型 p53 衍生肽混合物，并使用干扰素-γ酶联免疫斑点测定进行评估。流式细胞术用于分析 T 细胞亚群和表达免疫检查点分子的 T 细胞的比例。
在 23 例患者中的 22 例（95.7%）中检测到 HPV E6/E7 特异性 T 细胞，而在 20 例患者中的 3 例（15.0%）中检测到野生型 p53 特异性 T 细胞。使用全蛋白而非肽，在 16 例患者中的 7 例（43.8%）中检测到野生型 p53 特异性 T 细胞反应。在 20 例患者中的 9 例（45.0%）中，免疫检查点阻断增强了野生型 p53 特异性 T 细胞反应。PBMC 的流式细胞分析显示，在免疫检查点阻断后表现出增强的野生型 p53 特异性 T 细胞反应的应答者中，Ki-67+CD4+T 细胞、Ki-67+CD8+T 细胞、调节性 T 细胞、PD-1+CD4+T 细胞和 TIM-3+CD4+T 细胞的比例明显更高。
我们的发现表明，HPV 阳性 HNSCC 患者的外周血中存在肿瘤抗原特异性 T 细胞。阻断检查点途径可以增强某些患者的 T 细胞反应，可能是通过激活的 T 细胞、Tregs 和/或耗竭的 CD4+T 细胞。
