Functional HPV-specific PD-1(+) stem-like CD8 T cells in head and neck cancer.
Functional HPV-specific PD-1(+) stem-like CD8 T cells in head and neck cancer.
复制标题
头颈部肿瘤中功能性HPV特异性PD-1(+)干细胞样CD8 T细胞的研究
DOI：
10.1038/s41586-021-03862-z
复制
发表时间：
2021-09
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
T细胞在肿瘤免疫中很重要，但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）阳性头颈癌患者的CD 8 T细胞，并确定了几个来自HPV E2，E5和E6蛋白的表位，使我们能够使用主要组织相容性复合体（MHC）I类四聚体分析病毒特异性CD 8 T细胞。HPV特异性CD 8 T细胞表达PD-1，并且在肿瘤中可检测到，对于给定表位，肿瘤浸润性CD 8 T淋巴细胞（TIL）的水平范围为0.1%至10%。四聚体分选的HPV特异性PD-1+ CD 8 TIL的单细胞RNA测序分析揭示了三个转录上不同的子集。一个子集表达TCF 7和与PD-1+干细胞样CD 8 T细胞相关的其他基因，这些基因对于在抗原持续存在的条件下维持T细胞应答至关重要。第二个子集表达更多的效应分子，代表一个短暂的细胞群体，第三个子集的特征是终末分化的基因签名。T细胞受体克隆型之间共享的三个子集和伪时间分析表明一个假设的分化轨迹从干细胞样的过渡到终末分化的细胞。更值得注意的是，HPV特异性PD-1+TCF-1+干细胞样TIL在用同源HPV肽体外刺激后增殖并分化成更多的效应细胞样细胞，而更多的终末分化细胞不增殖。具有增殖能力的功能性HPV特异性PD-1+TCF-1+ CD 45 RO+干细胞样CD 8 T细胞的存在表明，HPV阳性头颈癌中存在对PD-1阻断反应的细胞机制，支持进一步研究PD-1靶向治疗这种恶性肿瘤。此外，HPV治疗性疫苗接种工作集中在E6和E7蛋白;我们的研究结果表明，E2和E5也应该被考虑作为疫苗抗原，以引起最大宽度的肿瘤反应性CD 8 T细胞应答。
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-1+TCF-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-1+TCF-1+CD45RO+ 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.
登录
查看更多内容
影响因子：
3
作者：
DeTomaso D;Yosef N
通讯作者：
Yosef N
影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
64.8
作者：
Simoni, Yannick;Becht, Etienne;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
16.6
作者：
Rosato, Pamela C.;Wijeyesinghe, Sathi;Masopust, David
通讯作者：
Masopust, David