Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
J Immunother Cancer. 2024 Jun 10;12(6):e008667. doi: 10.1136/jitc-2023-008667.
Oropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC remain unclear.
To identify the cellular and molecular factors that limited the benefits associated with HPV in OPSCC immunotherapy, we performed single-cell RNA (n=20) and T-cell receptor sequencing (n=10) analyses of tonsil or base of tongue tumor biopsies prior to immunotherapy. Primary findings from our single-cell analysis were confirmed through immunofluorescence experiments, and secondary validation analysis were performed via publicly available transcriptomics data sets.
We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. We also observed a significantly larger proportion of CD4 follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8 resident memory T cells (Trm) with elevated (encoding CD161) expression showed an association with dampened antitumor activity in patients with HPV-positive OPSCC, which may explain their heterogeneous clinical outcomes. Notably, all HPV-positive patients, whose Trm presented elevated levels, showed low expression of (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade showed an inverse correlation between the density of CD161 Trm and changes in tumor size.
We found that CD161 Trm counteracts clinical benefits associated with HPV in OPSCC immunotherapy. This suggests that targeted inhibition of CD161 in Trm could enhance the efficacy of immunotherapy in HPV-positive oropharyngeal cancers.
NCT03737968.
人乳头瘤病毒（HPV 阳性）引起的口咽鳞状细胞癌（OPSCC）与 HPV 阴性 OPSCC 相比，具有更好的临床结局。然而，HPV 阳性 OPSCC 患者免疫治疗的临床获益仍不清楚。
为了确定限制 HPV 阳性 OPSCC 免疫治疗获益的细胞和分子因素，我们在免疫治疗前对扁桃体或舌根肿瘤活检进行了单细胞 RNA（n=20）和 T 细胞受体测序（n=10）分析。通过免疫荧光实验验证了我们单细胞分析的主要发现，并通过公开的转录组数据集进行了二次验证分析。
我们发现，无论 HPV 感染状态如何，免疫治疗无应答者的恶性细胞转录多样性显著更高。我们还观察到 HPV 阳性肿瘤中 CD4 滤泡辅助 T 细胞（Tfh）的比例明显更大，这可能是由于 Tfh 分化增强所致。最重要的是，表达水平升高的 CD8 驻留记忆 T 细胞（Trm）与 HPV 阳性 OPSCC 患者的抗肿瘤活性减弱有关，这可能解释了它们异质性的临床结局。值得注意的是，所有 HPV 阳性患者的 Trm 呈现升高的 表达水平，其 B 细胞中表达（编码 CD161 配体）水平较低，这可能会降低三级淋巴结构的活性。免疫检查点阻断治疗的 HPV 阳性肿瘤的免疫荧光显示，CD161 Trm 密度与肿瘤大小变化呈负相关。
我们发现 CD161 Trm 对抗 HPV 阳性 OPSCC 免疫治疗的临床获益。这表明靶向抑制 Trm 中的 CD161 可能增强 HPV 阳性口咽癌免疫治疗的疗效。
NCT03737968。
Zotero 插件
