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May 15, 2018

Exhausted T Cells Come in Different Flavors

Disease-specific features of exhausted T cells have been revealed by epigenomic-guided mass cytometry profiling. Exhausted T cells have poor function in chronic infections and cancer but can be therapeutically reinvigorated. [John Wherry/Perelman School of Medicine at the University of Pennsylvania]

  • Connoisseurs of exhausted T cells, or Tex cells, may acquire the ability to recognize distinct disease histories. A discrete lineage of Tex cells, it turns out, may emit an epigenetic bouquet particular to a type of disease—a viral infection or cancer, for example. Already, nine distinct types of Tex cells have been identified by researchers at the University of Pennsylvania.

    In recent years, these researchers have been sensitizing themselves to key features of T-cell exhaustion, which include increased expression of inhibitory receptors, reduced cytokine production, weakened cell proliferation potential, and altered transcriptional program/epigenetic landscape. And now these researchers report that they have developed an assay to investigate the molecules that control gene expression in Tex cells.

    Details appeared May 15 in the journal Immunity, in an article entitled “Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells.” This article describes how the researchers defined core exhaustion-specific genes and identified disease-induced molecular changes in Tex cell populations in HIV with uncontrolled disease and in human lung cancer.

    “...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,” the article’s authors wrote. “Single-cell proteomic profiling identified at least 9 distinct TEX clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns.”

    Long-term, persisting infections and other chronic diseases such as cancer can result in a prolonged stalemate. Over time, weary T cells become exhausted, giving germs or tumors an edge. This immunological struggle, it happens, leaves molecular traces.

    “Our lab is interested in the population dynamics, transcriptional/epigenetic stochastic, and molecular regulation mechanism during T-cell exhaustion development,” notes the website maintained by the University of Pennsylvania’s laboratory of John Wherry, Ph.D., a professor of microbiology and director of the Institute for Immunology. “By understanding these mechanisms, we aim to enhance T-cell immunity and provide better therapeutic strategies for clinical application.”

    Dr. Wherry's lab has spent the last decade describing these populations of fatigued cells. Overall, when normal T cells become exhausted, they develop defects in their germ- and tumor-fighting capabilities. Tex also express inhibitory receptor proteins on their surface that stall key biochemical pathways, provoke changes in control of gene expression, alter metabolism for making energy to fight infections and tumors, and prevent development of optimal immune function.

    "Tex cells are a discrete cell lineage that have become important immunotherapy targets for chronic infection and cancer," added Dr. Werry, who is the senior author of the current study. "Now, we know that Tex cells are a vastly diverse set of immune cells."

    New, highly effective immunotherapies that target these inhibitory receptors expressed by Tex, such as programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4), have shown dramatic effects among patients with melanoma and other diseases, with potential to also combat breast, ovarian, and other cancers. Although Tex have been implicated in the response to checkpoint blockade drugs in animal models, the underlying immunological mechanisms of their therapeutic response or failure in people is only now being studied in earnest.

    "Tex cells are quite diverse, as are all types of T cells," Dr. Wherry said. "This sheer diversity is the hallmark of the human immune system that has to essentially have a way to respond to every germ an individual might encounter in a lifetime."

    Knowing this, the Penn team asked what the diversity in the Tex pool reveals about a disease itself and its course in a patient. They developed an assay to investigate the molecules that control gene expression in Tex by comparing them to other types of T cells and within a Tex population in blood from HIV patients whose viral load is well controlled.

    Because of the clusters' relationships to specific disease type and progression, the team's aim is to use the signature of a Tex cluster to assess a patient's overall immune health and likelihood of responding to a certain therapy. "We want to be able to select and tailor immune therapies according to a patient's Tex-cell pool and its individual characteristics," Wherry said.

    Applying this type of assessment to Tex cells in the context of immunotherapy clinical trials might identify patients more likely to benefit from specific types of combination immunotherapies and may point to underlying mechanisms in the specific types of Tex cells responding to an infection or cancer.

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