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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.

SUBMITTER: Brummelman J 

PROVIDER: S-EPMC6170179 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Brummelman Jolanda J   Mazza Emilia M C EMC   Alvisi Giorgia G   Colombo Federico S FS   Grilli Andrea A   Mikulak Joanna J   Mavilio Domenico D   Alloisio Marco M   Ferrari Francesco F   Lopci Egesta E   Novellis Pierluigi P   Veronesi Giulia G   Lugli Enrico E  

The Journal of experimental medicine 20180828 10


CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> TIM-3<sup>-</sup> CD8<sup>+</sup> T cells with a partial exhausted  ...[more]

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