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Science Immunology  01 Jun 2018:
Vol. 3, Issue 24, eaau2260
DOI: 10.1126/sciimmunol.aau2260

Abstract

High-dimensional profiling defines novel metrics of T cell exhaustion in HIV and cancer.

An optimal CD8+ T cell response is essential to combat both chronic infections and cancer. A key mechanism of immune escape shared by chronic pathogens and tumor cells is induction of functional exhaustion in CD8+ T cells (Tex). Conventional immunophenotyping techniques often generate species-restricted and vaguely defined human Tex profiles, with little correlation to disease severity or treatment outcomes. Generating more broadly relevant Tex profiles that correlate accurately with clinical outcomes would be of great translational relevance in immune monitoring. In this article, Bengsch and colleagues report a novel, translationally robust method to generate T cell functional profiles, integrating deep mass cytometry (CyTOF) with genomic and epigenomic bioinformatic analysis of Tex cells in the mouse chronic lymphocytic choriomeningitis virus (LCMV) system. The authors first identified signatures associated with LCMV-specific Tex cells during chronic infection compared with nave T cells (TN), T effector cells (TEFF), and memory T cells (TMEM) in acute resolving infection, mapping at least nine distinct Tex profile clusters in mice. From this a functional exhaustion score (FES) was developed that was increased in Tex [for example, loss-of-tumor necrosis factor-α (TNF-α) or interleukin-2 production] and decreased with effector or memory function [for example, interferon (IFN)-γ and TNF-α coproduction]. The preliminary FES was then broadly validated by interrogating peripheral blood mononuclear cells from healthy adults, HIV progressor patients versus HIV elite controllers, and lung cancer patients in various stages of treatment and response. Across this very broad validation population, the high-dimensional approach dependably differentiated Tex cells from TEFF, a distinction difficult to achieve using classical immunophenotyping.

These data demonstrate the power of an epigenomically guided cytometry by time-of-flight approach to connect the landscape of specific T cell functional profiles across species, disease type, disease severity and treatment responses. Such a multidimensional systems immunology approach has profound implications for deeper interrogation of human T cell lineage specification, differentiation, and activation status during and after therapeutic interventions. For example, one novel application might be in probing Tex profiles before and after checkpoint blockade in cancer patients to monitor response and guide changes in therapy. Deeper advancement of such a multidimensional approach will be a powerful tool in future immune monitoring and theranostics in autoimmunity, infections, and cancer.

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