Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
Nature. 2021 Sep;597(7875):279-284. doi: 10.1038/s41586-021-03862-z. Epub 2021 Sep 1.
T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1 CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1 stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1TCF-1 stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1TCF-1CD45RO stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.
T 细胞在肿瘤免疫中很重要，但人们需要更好地了解人类癌症中抗原特异性 T 细胞的分化。在这里，我们研究了人乳头瘤病毒 (HPV) 阳性头颈部癌症患者的 CD8 T 细胞，并鉴定了来自 HPV E2、E5 和 E6 蛋白的几个表位，这些表位使我们能够使用主要组织相容性复合物 (MHC) Ⅰ类四聚体分析病毒特异性 CD8 T 细胞。HPV 特异性 CD8 T 细胞表达 PD-1，在肿瘤中可检测到，其水平范围为给定表位的肿瘤浸润性 CD8 T 淋巴细胞 (TIL) 的 0.1%至 10%。四聚体分选的 HPV 特异性 PD-1 CD8 TIL 的单细胞 RNA 测序分析揭示了三个转录上不同的亚群。一个亚群表达 TCF7 和其他与 PD-1 干性 CD8 T 细胞相关的基因，这些基因对于在抗原持续存在的情况下维持 T 细胞反应至关重要。第二个亚群表达更多的效应分子，代表一个过渡细胞群体，第三个亚群的特征是终末分化的基因特征。三个亚群之间共享 T 细胞受体克隆型，拟时分析表明从干性到过渡到终末分化细胞的假设分化轨迹。更值得注意的是，HPV 特异性 PD-1TCF-1 干性 TIL 在体外与同源 HPV 肽刺激后增殖并分化为更具效应器样的细胞，而更终末分化的细胞则不增殖。存在具有增殖能力的功能性 HPV 特异性 PD-1TCF-1CD45RO 干性 CD8 T 细胞表明存在对 PD-1 阻断作出反应的细胞机制存在于 HPV 阳性头颈部癌症中，支持进一步研究这种恶性肿瘤的 PD-1 靶向治疗。此外，HPV 治疗性疫苗接种的重点是 E6 和 E7 蛋白；我们的结果表明，E2 和 E5 也应被考虑作为疫苗抗原，以引发最大广度的肿瘤反应性 CD8 T 细胞反应。
