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

• Published in: The Journal of experimental medicine Vol. 215; no. 10; pp. 2520 - 2535
• Main Authors: Brummelman, Jolanda, Mazza, Emilia M.C., Alvisi, Giorgia, Colombo, Federico S., Grilli, Andrea, Mikulak, Joanna, Mavilio, Domenico, Alloisio, Marco, Ferrari, Francesco, Lopci, Egesta, Novellis, Pierluigi, Veronesi, Giulia, Lugli, Enrico
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.10.2018
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20180684

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.