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

Nathan D. Mathewson; Orr Ashenberg; Itay Tirosh; Simon Gritsch; Elizabeth M. Perez; Sascha Marx; Livnat Jerby-Arnon; Rony Chanoch-Myers; Toshiro Hara; Alyssa R. Richman; Yoshinaga Ito; Jason Pyrdol; Mirco Friedrich; Kathrin Schumann; Michael J. Poitras; Prafulla C. Gokhale; L. Nicolas Gonzalez Castro; Marni E. Shore; Christine M. Hebert; Brian Shaw; Heather L. Cahill; Matthew Drummond; Wubing Zhang; Olamide Olawoyin; Hiroaki Wakimoto; Orit Rozenblatt-Rosen; Priscilla K. Brastianos; X. Shirley Liu; Pamela S. Jones; Daniel P. Cahill; Matthew P. Frosch; David N. Louis; Gordon J. Freeman; Keith L. Ligon; Alexander Marson; E. Antonio Chiocca; David A. Reardon; Aviv Regev; Mario L. Suvà; Kai W. Wucherpfennig

doi:10.1016/j.cell.2021.01.022

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

Nathan D. Mathewson, Orr Ashenberg, Itay Tirosh, Simon Gritsch, Elizabeth M. Perez, Sascha Marx, Livnat Jerby-Arnon, Rony Chanoch-Myers, Toshiro Hara, Alyssa R. Richman, Yoshinaga Ito, Jason Pyrdol, Mirco Friedrich, Kathrin Schumann, Michael J. Poitras, Prafulla C. Gokhale, L. Nicolas Gonzalez Castro, Marni E. Shore, Christine M. Hebert, Brian ShawHeather L. Cahill, Matthew Drummond, Wubing Zhang, Olamide Olawoyin, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Priscilla K. Brastianos, X. Shirley Liu, Pamela S. Jones, Daniel P. Cahill, Matthew P. Frosch, David N. Louis, Gordon J. Freeman, Keith L. Ligon, Alexander Marson, E. Antonio Chiocca, David A. Reardon, Aviv Regev, Mario L. Suvà, Kai W. Wucherpfennig

Department of Molecular Cell Biology

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1281-1298
Number of pages	18
Journal	Cell
Volume	184
Issue number	5
Early online date	15 Feb 2021
DOIs	https://doi.org/10.1016/j.cell.2021.01.022
State	Published - 4 Mar 2021

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2021.01.022

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Mathewson, N. D., Ashenberg, O., Tirosh, I., Gritsch, S., Perez, E. M., Marx, S., Jerby-Arnon, L., Chanoch-Myers, R., Hara, T., Richman, A. R., Ito, Y., Pyrdol, J., Friedrich, M., Schumann, K., Poitras, M. J., Gokhale, P. C., Gonzalez Castro, L. N., Shore, M. E., Hebert, C. M., ... Wucherpfennig, K. W. (2021). Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell, 184(5), 1281-1298. https://doi.org/10.1016/j.cell.2021.01.022

@article{7be22ee5c28546c49b97567932837f55,

title = "Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis",

abstract = "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. ",

author = "Mathewson, \{Nathan D.\} and Orr Ashenberg and Itay Tirosh and Simon Gritsch and Perez, \{Elizabeth M.\} and Sascha Marx and Livnat Jerby-Arnon and Rony Chanoch-Myers and Toshiro Hara and Richman, \{Alyssa R.\} and Yoshinaga Ito and Jason Pyrdol and Mirco Friedrich and Kathrin Schumann and Poitras, \{Michael J.\} and Gokhale, \{Prafulla C.\} and \{Gonzalez Castro\}, \{L. Nicolas\} and Shore, \{Marni E.\} and Hebert, \{Christine M.\} and Brian Shaw and Cahill, \{Heather L.\} and Matthew Drummond and Wubing Zhang and Olamide Olawoyin and Hiroaki Wakimoto and Orit Rozenblatt-Rosen and Brastianos, \{Priscilla K.\} and Liu, \{X. Shirley\} and Jones, \{Pamela S.\} and Cahill, \{Daniel P.\} and Frosch, \{Matthew P.\} and Louis, \{David N.\} and Freeman, \{Gordon J.\} and Ligon, \{Keith L.\} and Alexander Marson and Chiocca, \{E. Antonio\} and Reardon, \{David A.\} and Aviv Regev and Suv{\`a}, \{Mario L.\} and Wucherpfennig, \{Kai W.\}",

year = "2021",

month = mar,

day = "4",

doi = "10.1016/j.cell.2021.01.022",

language = "الإنجليزيّة",

volume = "184",

pages = "1281--1298",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

}

Mathewson, ND, Ashenberg, O, Tirosh, I, Gritsch, S, Perez, EM, Marx, S, Jerby-Arnon, L, Chanoch-Myers, R, Hara, T, Richman, AR, Ito, Y, Pyrdol, J, Friedrich, M, Schumann, K, Poitras, MJ, Gokhale, PC, Gonzalez Castro, LN, Shore, ME, Hebert, CM, Shaw, B, Cahill, HL, Drummond, M, Zhang, W, Olawoyin, O, Wakimoto, H, Rozenblatt-Rosen, O, Brastianos, PK, Liu, XS, Jones, PS, Cahill, DP, Frosch, MP, Louis, DN, Freeman, GJ, Ligon, KL, Marson, A, Chiocca, EA, Reardon, DA, Regev, A, Suvà, ML & Wucherpfennig, KW 2021, 'Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis', Cell, vol. 184, no. 5, pp. 1281-1298. https://doi.org/10.1016/j.cell.2021.01.022

TY - JOUR

T1 - Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

AU - Mathewson, Nathan D.

AU - Ashenberg, Orr

AU - Tirosh, Itay

AU - Gritsch, Simon

AU - Perez, Elizabeth M.

AU - Marx, Sascha

AU - Jerby-Arnon, Livnat

AU - Chanoch-Myers, Rony

AU - Hara, Toshiro

AU - Richman, Alyssa R.

AU - Ito, Yoshinaga

AU - Pyrdol, Jason

AU - Friedrich, Mirco

AU - Schumann, Kathrin

AU - Poitras, Michael J.

AU - Gokhale, Prafulla C.

AU - Gonzalez Castro, L. Nicolas

AU - Shore, Marni E.

AU - Hebert, Christine M.

AU - Shaw, Brian

AU - Cahill, Heather L.

AU - Drummond, Matthew

AU - Zhang, Wubing

AU - Olawoyin, Olamide

AU - Wakimoto, Hiroaki

AU - Rozenblatt-Rosen, Orit

AU - Brastianos, Priscilla K.

AU - Liu, X. Shirley

AU - Jones, Pamela S.

AU - Cahill, Daniel P.

AU - Frosch, Matthew P.

AU - Louis, David N.

AU - Freeman, Gordon J.

AU - Ligon, Keith L.

AU - Marson, Alexander

AU - Chiocca, E. Antonio

AU - Reardon, David A.

AU - Regev, Aviv

AU - Suvà, Mario L.

AU - Wucherpfennig, Kai W.

PY - 2021/3/4

Y1 - 2021/3/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85101668184&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.01.022

DO - 10.1016/j.cell.2021.01.022

M3 - مقالة

C2 - 33592174

SN - 0092-8674

VL - 184

SP - 1281

EP - 1298

JO - Cell

JF - Cell

IS - 5

ER -

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

Abstract

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