High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors.
High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors.
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DOI：
10.1084/jem.20180684
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Lugli E
中科院分区：
文献类型：
--
作者：
Brummelman J;Mazza EMC;Alvisi G;Colombo FS;Grilli A;Mikulak J;Mavilio D;Alloisio M;Ferrari F;Lopci E;Novellis P;Veronesi G;Lugli E
浸润肿瘤的CD 8 + T细胞在很大程度上功能失调。Brummelman和Mazza等人鉴定了部分耗尽的CXCR 5 + TIM-3-CD 8 + T细胞，其具有增强的干细胞样性质和细胞毒性浸润人实体瘤。这些细胞表达候选免疫学靶标（PD-1、TIGIT和CD 27）以用于它们的再活化。浸润肿瘤的CD 8 + T细胞在很大程度上是功能失调的，但一个亚群是否保持上级功能仍然不清楚。通过对来自53名肺癌患者的数百万CD 8 + T细胞进行高维单细胞分析，我们定义了与无癌组织和血液相比在肿瘤中富集的那些亚群。除了耗尽和活化的细胞，我们还鉴定了具有部分耗尽表型的CXCR 5 + TIM-3-CD 8 + T细胞，同时保留了负责干细胞样可塑性和细胞毒性的基因网络，如通过全转录组的单细胞测序所揭示的。离体，CXCR 5 + TIM-3-CD 8 + T细胞与分化程度更高的亚群相比显示出增强的自我更新和多能性，并且在很大程度上是多功能的。抑制性和共刺激受体的分析揭示了PD-1、TIGIT和CD 27作为免疫疗法的可能靶标。因此，我们证明了在人类癌症中T细胞耗竭的背景下分化的层次结构，类似于慢性感染的小鼠，其进一步显示随着疾病进展而消失。
CD8+ T cells infiltrating tumors are largely dysfunctional. Brummelman and Mazza et al. identify partially exhausted CXCR5+ TIM-3– CD8+ T cells with enhanced stem-like properties and cytotoxicity infiltrating human solid tumors. These cells express candidate immunotherapeutic targets (PD-1, TIGIT and CD27) for their reinvigoration. CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5+ TIM-3– CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome. Ex vivo, CXCR5+ TIM-3– CD8+ T cells displayed enhanced self-renewal and multipotency compared with more differentiated subsets and were largely polyfunctional. Analysis of inhibitory and costimulatory receptors revealed PD-1, TIGIT, and CD27 as possible targets of immunotherapy. We thus demonstrate a hierarchy of differentiation in the context of T cell exhaustion in human cancer similar to that of chronically infected mice, which is further shown to disappear with disease progression.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
64.5
作者：
Levine JH;Simonds EF;Bendall SC;Davis KL;Amir el-AD;Tadmor MD;Litvin O;Fienberg HG;Jager A;Zunder ER;Finck R;Gedman AL;Radtke I;Downing JR;Pe'er D;Nolan GP
通讯作者：
Nolan GP
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：
4.3
作者：
Chen H;Lau MC;Wong MT;Newell EW;Poidinger M;Chen J
通讯作者：
Chen J
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