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J Exp Med. 2018 Oct 1;215(10):2520-2535. doi: 10.1084/jem.20180684. Epub 2018 Aug 28.

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

Author information

1
Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
2
Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
3
Department of Biological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
4
PhD Program of Molecular and Translational Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, Italy.
5
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
6
Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
7
Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
8
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
9
Nuclear Medicine Department, Humanitas Clinical and Research Hospital, Milan, Italy.
10
Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy enrico.lugli@humanitasresearch.it.

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.

PMID:
30154266
PMCID:
PMC6170179
DOI:
10.1084/jem.20180684
[Indexed for MEDLINE]
Free PMC Article

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