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

The Journal of Experimental Medicine
Jolanda BrummelmanEnrico Lugli

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.

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Citations

Feb 5, 2019·The Journal of Clinical Investigation·Enrico LugliGiovanni Galletti
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Datasets Mentioned

BETA
GSE84105
GSM2227314

Methods Mentioned

BETA
flow cytometry
scRNA-seq
flow
dissection
FACS
FCS
chip
RNaseq
PMA

Software Mentioned

SPICE
CyTOF
tSNE
limma
cytofkit
gplots R package
Bioconductor
GraphPad Prism
Seurat R package
GSEA

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