Epigenomic‐Guided Mass Cytometry Profiling Reveals Disease‐Specific Features of Exhausted CD8 T Cells

SUMMARY Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a transcriptomic‐ and epigenetic‐guided mass cytometry approach to define core exhaustion‐specific genes and disease‐induced changes in Tex cells in HIV and human cancer. Single‐cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co‐expression patterns. An exhaustion severity metric was developed and integrated with high‐dimensional phenotypes to define Tex cell clusters that were present in healthy subjects, common across chronic infection and cancer or enriched in either disease, linked to disease severity, and changed with HIV therapy. Combinatorial patterns of immunotherapy targets on different Tex cell clusters were also defined. This approach and associated datasets present a resource for investigating human Tex cell biology, with implications for immune monitoring and immunomodulation in chronic infections, autoimmunity, and cancer. Graphical Abstract Figure. No Caption available. HighlightsUnbiased identification of unique Tex genes using transcriptomics and epigenomicsHigh‐dimensional CyTOF profiling of human Tex gene products reveals heterogeneityIdentification of key disease‐relevant Tex cell populations in HIV and lung cancerDevelopment of exhaustion metrics applicable to human immune monitoring &NA; Exhausted T (Tex) cells have poor function in chronic infections and cancer but can be therapeutically re‐invigorated. Bengsch et al. use genes modified epigenetically during exhaustion and high‐dimensional CyTOF profiling to define Tex cell heterogeneity in humans with HIV or lung cancer and link Tex cell features to disease progression and response to immunotherapy.