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jem Home » 2018 Archive » 1 October » 215 (10): 2520
Article

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

View ORCID ProfileJolanda Brummelman, Emilia M.C. Mazza, Giorgia Alvisi, View ORCID ProfileFederico S. Colombo, View ORCID ProfileAndrea Grilli, Joanna Mikulak, View ORCID ProfileDomenico Mavilio, Marco Alloisio, Francesco Ferrari, Egesta Lopci, Pierluigi Novellis, Giulia Veronesi, View ORCID ProfileEnrico Lugli  Correspondence email
Jolanda Brummelman
Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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  • ORCID record for Jolanda Brummelman
Emilia M.C. Mazza
Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Giorgia Alvisi
Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Federico S. Colombo
Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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  • ORCID record for Federico S. Colombo
Andrea Grilli
Department of Biological Sciences, University of Modena and Reggio Emilia, Modena, ItalyPhD Program of Molecular and Translational Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, Italy
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Joanna Mikulak
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, ItalyDepartment of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
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Domenico Mavilio
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, ItalyDepartment of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
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Marco Alloisio
Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Francesco Ferrari
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
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Egesta Lopci
Nuclear Medicine Department, Humanitas Clinical and Research Hospital, Milan, Italy
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Pierluigi Novellis
Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Giulia Veronesi
Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Enrico Lugli
Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, ItalyHumanitas Flow Cytometry Core, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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  • ORCID record for Enrico Lugli
  • For correspondence: enrico.lugli@humanitasresearch.it
DOI: 10.1084/jem.20180684 | Published August 28, 2018
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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.

  • Submitted: 11 April 2018
  • Revision received 6 July 2018
  • Accepted: 16 August 2018
Creative Commons logoCreative Commons logohttp://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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© 2018 Brummelman et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors
Jolanda Brummelman, Emilia M.C. Mazza, Giorgia Alvisi, Federico S. Colombo, Andrea Grilli, Joanna Mikulak, Domenico Mavilio, Marco Alloisio, Francesco Ferrari, Egesta Lopci, Pierluigi Novellis, Giulia Veronesi, Enrico Lugli
Journal of Experimental Medicine Oct 2018, 215 (10) 2520-2535; DOI: 10.1084/jem.20180684

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The Journal of Experimental Medicine: 216 (2)

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February 4, 2019
Volume 216, No. 2

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