High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors

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Abstract

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.

Original languageEnglish
Pages (from-to)2520-2535
Number of pages16
JournalThe Journal of experimental medicine
Volume215
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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Single-Cell Analysis
T-Lymphocytes
Neoplasms
Programmed Cell Death 1 Receptor
Gene Regulatory Networks
Transcriptome
Immunotherapy
Disease Progression
Lung Neoplasms
Phenotype

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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title = "High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors",
abstract = "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.",
author = "Jolanda Brummelman and Mazza, {Emilia M.C.} and Giorgia Alvisi and Colombo, {Federico S.} and Andrea Grilli and Joanna Mikulak and Domenico Mavilio and Marco Alloisio and Francesco Ferrari and Egesta Lopci and Pierluigi Novellis and Giulia Veronesi and Enrico Lugli",
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T1 - High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors

AU - Brummelman, Jolanda

AU - Mazza, Emilia M.C.

AU - Alvisi, Giorgia

AU - Colombo, Federico S.

AU - Grilli, Andrea

AU - Mikulak, Joanna

AU - Mavilio, Domenico

AU - Alloisio, Marco

AU - Ferrari, Francesco

AU - Lopci, Egesta

AU - Novellis, Pierluigi

AU - Veronesi, Giulia

AU - Lugli, Enrico

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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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