Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.
Cancer Immunol Res. 2023 Mar 1;11(3):306-319. doi: 10.1158/2326-6066.CIR-22-0454.
Human papillomavirus (HPV)-driven oropharyngeal carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC and has a unique immune landscape. Studies have supported the heterogeneity of T cells, accompanied by a broad repertoire of T-cell responses, within tumors driven by HPV infection. However, the phenotype and function of these HPV-related T cells remain unclear. Using a combination of single-cell RNA sequencing, flow cytometry, pharmacologic inhibition, and immunofluorescence staining, we explored the prognostic implication of HPV-related T cells and further validated our findings in two independent cohorts. Cytotoxic T lymphocytes (CTL) within OPSCC displayed a spectrum of transcriptional signatures. Among which, we identified CD161 receptor, encoded by KLRB1, as a potential marker to distinguish the CTL subsets in HPV-positive OPSCC with a divergent evolutionary trajectory. In-depth analysis revealed that CD161+ CTLs exhibited a more robust immune response over the CD161- counterparts and a T cell-inflamed phenotype that could be further reinvigorated by immune-checkpoint blockade. Despite the high expression of exhaustion markers, reinforcement of CD161+ CTL reactivity was expected to boost immune responses, considering their functional reversibility. We further confirmed that the high level of intratumoral CD161+ CTLs associated with a favorable treatment response and prolonged overall survival. Therefore, our research not only provides an insight into the immune landscape of HPV-driven OPSCC but also sheds light on a special subset of CTLs with prognostic and therapeutic significance.
人乳头瘤病毒（HPV）驱动的口咽癌（OPSCC）与烟草或酒精相关的 OPSCC 不同，具有独特的免疫景观。研究支持 HPV 感染驱动的肿瘤内 T 细胞的异质性，伴随着广泛的 T 细胞反应 repertoire。然而，这些 HPV 相关 T 细胞的表型和功能仍不清楚。我们使用单细胞 RNA 测序、流式细胞术、药理抑制和免疫荧光染色相结合的方法，探索了 HPV 相关 T 细胞的预后意义，并在两个独立的队列中进一步验证了我们的发现。OPSCC 中的细胞毒性 T 淋巴细胞（CTL）表现出一系列转录特征。其中，我们确定了 CD161 受体，由 KLRB1 编码，作为一种潜在的标志物，以区分 HPV 阳性 OPSCC 中具有不同进化轨迹的 CTL 亚群。深入分析表明，CD161+CTL 表现出更强的免疫反应，而 CD161-CTL 则表现出更强的免疫反应，并且可以通过免疫检查点阻断进一步增强。尽管高表达衰竭标志物，但考虑到 CD161+CTL 反应的功能可逆性，增强 CD161+CTL 反应有望增强免疫反应。我们进一步证实，肿瘤内高水平的 CD161+CTL 与良好的治疗反应和延长的总生存期相关。因此，我们的研究不仅提供了对 HPV 驱动的 OPSCC 免疫景观的深入了解，还揭示了具有预后和治疗意义的特殊 CTL 亚群。
