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

Research output: Contribution to journalArticlepeer-review

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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