Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

被引：290

作者：

Mathewson, Nathan D. ^{[1
,2
,3
,4
]}

Ashenberg, Orr ^{[4
,5
]}

Tirosh, Itay ^{[6
]}

Gritsch, Simon ^{[4
,5
,7
,8
]}

Perez, Elizabeth M. ^{[4
,5
,7
,8
,9
]}

Marx, Sascha ^{[1
,2
]}

Jerby-Arnon, Livnat ^{[4
,5
,10
,11
]}

Chanoch-Myers, Rony ^{[6
]}

Hara, Toshiro ^{[4
,5
,7
,8
]}

Richman, Alyssa R. ^{[4
,5
,7
,8
]}

Ito, Yoshinaga ^{[1
,2
]}

Pyrdol, Jason ^{[1
]}

Friedrich, Mirco ^{[1
]}

Schumann, Kathrin ^{[12
,13
]}

Poitras, Michael J. ^{[14
,15
]}

Gokhale, Prafulla C. ^{[14
,15
]}

Castro, L. Nicolas Gonzalez ^{[3
,4
,5
,7
,8
,16
]}

Shore, Marni E. ^{[4
,5
,7
,8
]}

Hebert, Christine M. ^{[4
,5
,7
,8
]}

Shaw, Brian ^{[17
,18
,19
,20
]}

Cahill, Heather L. ^{[7
,8
]}

Drummond, Matthew ^{[7
,8
]}

Zhang, Wubing ^{[21
]}

Olawoyin, Olamide ^{[1
]}

Wakimoto, Hiroaki ^{[22
,23
]}

Rozenblatt-Rosen, Orit ^{[4
,5
,24
]}

Brastianos, Priscilla K. ^{[17
,18
,19
,20
]}

Liu, X. Shirley ^{[21
]}

Jones, Pamela S. ^{[22
,23
]}

Cahill, Daniel P. ^{[22
,23
]}

Frosch, Matthew P. ^{[7
,8
]}

Louis, David N. ^{[7
,8
]}

Freeman, Gordon J. ^{[16
]}

Ligon, Keith L. ^{[25
]}

Marson, Alexander ^{[12
,26
,27
]}

Chiocca, E. Antonio ^{[28
]}

Reardon, David A. ^{[16
,29
]}

Regev, Aviv ^{[4
,5
,24
,30
]}

Suva, Mario L. ^{[4
,5
,7
,8
]}

Wucherpfennig, Kai W. ^{[1
,2
,3
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Immunol, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Div Neurol, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Broad Inst Harvard & MIT, Klarman Cell Observ, Cambridge, MA 02142 USA

[6] Weizmann Inst Sci, Dept Mol Cell Biol, IL-761001 Rehovot, Israel

[7] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[8] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[9] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[10] Stanford Univ, Dept Genet, Sch Med, Stanford, CA USA

[11] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

[12] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[13] Tech Univ Munchen TUM, Inst Med Microbiol Immunol & Hyg, Munich, Germany

[14] Dana Farber Canc Inst, Expt Therapeut Core, Boston, MA 02115 USA

[15] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA

[16] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[17] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Div Hematol Oncol,Canc Ctr, Boston, MA 02114 USA

[18] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Div Hematol Oncol,Canc Ctr, Boston, MA 02114 USA

[19] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Div Neurooncol,Canc Ctr, Boston, MA 02114 USA

[20] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Div Neurooncol,Canc Ctr, Boston, MA 02114 USA

[21] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Data Sci, Boston, MA USA

[22] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[23] Harvard Med Sch, Boston, MA 02114 USA

[24] Genentech Inc, San Francisco, CA 94080 USA

[25] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[26] Gladstone Inst, San Francisco, CA 94158 USA

[27] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[28] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA

[29] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[30] MIT, Koch Inst Integrat Canc Res, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

CELL | 2021年 / 184卷 / 05期

基金：

美国国家科学基金会; 日本学术振兴会;

关键词：

CD161; glioblastoma; IDH-mutant gliomas; single-cell RNA-seq; T cells;

D O I：

10.1016/j.cell.2021.01.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.

引用

页码：1281 / +

页数：44

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