小柯机器人

美国埃默里大学Rafi Ahmed、Andreas Wieland等研究人员合作发现头颈部癌症中的功能性HPV特异性PD-1⁺干细胞样CD8 T细胞。这一研究成果于2021年9月1日在线发表在国际学术期刊《自然》上。

研究人员揭示了人乳头瘤病毒（HPV）阳性头颈癌患者的CD8 T细胞，并确定了几个来自HPV E2、E5和E6蛋白的表位，这使得研究人员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CD8 T细胞。HPV特异性CD8 T细胞表达PD-1，在肿瘤中可检测到的水平为0.1%至10%的肿瘤浸润性CD8 T淋巴细胞（TIL）的特定表位。对四级分类的HPV特异性PD-1⁺ CD8 TIL的单细胞RNA测序分析显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久性条件下维持T细胞反应至关重要。第二个亚群表达更多的效应分子，代表了一个过渡性的细胞群，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，伪时间分析表明有一个假设的分化轨迹，即从干细胞到过渡性细胞再到最终分化的细胞。

更值得注意的是，HPV特异性PD-1⁺ TCF-1⁺干性TIL在体外接受同源HPV肽的刺激后，增殖并分化为更多的效应样细胞，而更多的终末分化细胞则没有增殖。功能性HPV特异性PD-1⁺ TCF-1⁺ CD45RO⁺干性CD8 T细胞的存在具有增殖能力，这表明在HPV阳性的头颈部癌症中存在响应PD-1阻断的细胞机制，从而支持对这种恶性肿瘤的PD-1靶向治疗进行进一步研究。此外，HPV治疗性疫苗接种工作主要集中在E6和E7蛋白上；这些结果表明，E2和E5也应被考虑作为疫苗抗原，可用于引起肿瘤反应性CD8 T细胞反应的最大范围。

据悉，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细胞的分化情况。

附：英文原文

Title: Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer

Author: Eberhardt, Christiane S., Kissick, Haydn T., Patel, Mihir R., Cardenas, Maria A., Prokhnevska, Nataliya, Obeng, Rebecca C., Nasti, Tahseen H., Griffith, Christopher C., Im, Se Jin, Wang, Xu, Shin, Dong M., Carrington, Mary, Chen, Zhuo G., Sidney, John, Sette, Alessandro, Saba, Nabil F., Wieland, Andreas, Ahmed, Rafi

Issue&Volume: 2021-09-01

Abstract: T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. 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. An analysis of human papillomavirus (HPV)-specific CD8 T cells in patients with head and neck cancer identifies functional PD-1+TCF-1+CD8 T cells in the tumour with implications for therapeutic vaccination and PD-1 directed immunotherapy.

DOI: 10.1038/s41586-021-03862-z

Source: https://www.nature.com/articles/s41586-021-03862-z

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