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.
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 factor, and EOMES,” the authors continued. “In addition, adoptive transfer of HDAC11KO T cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model.”
The goal for the GW team was to find a way to activate the T cells so that they could destroy the tumor. However, the process of cell activation does need to be refined and handled carefully.
“We don't want T cells to be easily activated, as they can cause harm to the host—the patient,” explained Dr. Sotomayor. “So, we want to look at possible methods and therapies to activate the T cells when they need to work.
“The next step is to perform preclinical studies with specific inhibitors of HDAC11 alone and in tandem with other existing immunotherapies, such as anti-PD-1/anti-PDL-1 [anti-programmed cell death protein 1/anti-programmed death-ligand 1] antibodies, in order to find the most potent combination. Our goal is to make the T cells better at destroying cancer tumors.”
This study represents a step forward in understanding the underlying mechanisms of T-cell function and epigenetic regulation of the HDAC11 enzyme. More importantly, this research highlights that HDAC11, which was the last of 11 HDACs to be discovered, should be treated as an immunotherapeutic target.