Epigenetic Checkpoint Control Could Boost T-Cell Antitumor Activity

저자：   업로드：2017-07-20  조회수：

    Histone deacetylase 11 (HDAC11), an epigenetic enzyme, has been identified as a potential immunotherapeutic target. According to researchers based at George Washington University (GWU), HDAC11 is a negative regulator of T-cell function. Specifically, T cells that express HDAC11 are relatively restrained, whereas T cells that lack HDAC11 are more aggressive, and more effective in destroying cancer cells.  T-cells can infiltrate tumors with the purpose of attacking the cancer cells. However, prior studies have found that the T-cells group around the tumor, but do not perform the job that they are meant to.

    The new findings appeared in the journal Blood, in an article entitled “T Cells Lacking HDAC11 Have Increased Effector Functions and Mediate Enhanced Alloreactivity in a Murine Model.” Although this article focused on the T cells around a lymphoma tumor, it describes T-cell behavior that could be pertinent to all types of cancer.

    "The goal of the T cell is to destroy the cancer tumor cells," said Eduardo M. Sotomayor, M.D., director of the GW Cancer Center and senior author of the study. "We wanted to look at and understand the mechanisms that allowed crosstalk between the tumor and the T-cells that stopped the T cells from doing their job."

    Dr. Sotomayor and colleagues decided to follow up on previous studies that had implicated histone acetylation, and the enzymes responsible for controlling these epigenetic marks, in regulating T-cell maturation and phenotype. Working with EGFP-HDAC11 transgenic reporter mice, the scientists found that HDAC11 expression was lower in effector relative to naïve and central memory T-cell populations. The scientists also observed that when resting T cells were activated, HDAC11 expression decreased.

    “Experiments using HDAC11 knockout (KO) mice revealed that T cells from these mice displayed enhanced proliferation, proinflammatory cytokine production, and effector molecule expression,” wrote the authors of the Blood article. “In addition, HDAC11KO T cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production.

    “In vivo, HDAC11KO T cells were refractory to tolerance induction. HDAC11KO T cells also mediated accelerated onset of acute graft-versus-host disease (GVHD) in a murine model, characterized by increased proliferation of T cells and expression of interferon-γ, tumor necrosis

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