High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors.
Jolanda BrummelmanEmilia M C MazzaGiorgia AlvisiFederico Simone ColomboAndrea GrilliJoanna MikulakDomenico MavilioMarco AlloisioFrancesco FerrariEgesta LopciPierluigi NovellisGiulia VeronesiEnrico LugliPublished in: The Journal of experimental medicine (2018)
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.
Keyphrases
- single cell
- rna seq
- endothelial cells
- papillary thyroid
- high throughput
- genome wide
- squamous cell
- induced pluripotent stem cells
- induced apoptosis
- gene expression
- peripheral blood
- pluripotent stem cells
- cell cycle arrest
- squamous cell carcinoma
- lymph node metastasis
- oxidative stress
- cell migration
- cell death
- metabolic syndrome
- adipose tissue
- insulin resistance
- young adults
- high fat diet induced