Researchers Explore Approaches to Block T-Cell Exhaustion


Expert discusses whether epigenetic programs regulate human T cell exhaustion and whether epigenetic-based strategies can be used to enhance T cell-based therapies.

Epigenetic modifications could allow researchers to block chimeric antigen receptor (CAR) T cells’ progression into exhaustion, according to a session at the 2022 International Cancer Immunotherapy Conference.

Using epigenetic modifications can reinforce gene expression programs associated with functional memory and T cell differentiation, according to speaker Benjamin Youngblood, PhD. Youngblood explained that naïve T cells become either terminal effector or memory precursor effectors, and these memory cells can then become functional memory cells.

By blocking certain processes, however, it is possible to stop the progression of these cells into exhaustion. Re-programming cells may also be possible, but at this point, Youngblood said there is a better understood process for blocking these effects.

“Epigenetics control the state the CD8 T-cell is in…and so what we’ve learned is that there has to be a very specific range of development that the T cell has to be in in order to mount a therapeutic response,” Youngblood said in an interview with Pharmacy Times.

When examining how long-lived gene expression programs are maintained in functional and exhausted CD8 T cells, Youngblood said there are 2 important concepts. First, mouse and human memory T cells persist in a quiescent state and maintain acquired epigenetic programs for years after their initial antigen encounter.

Second, epigenetic programs are causal in reinforcing the developmental state of T cell exhaustion. By knowing which programs are causal, researchers may be able to stop that transition.

De novo programs were able to restrict T cell expansion during programmed death cell-1 (PD-1) blockade therapy, illustrating that blocking DNMT3A was able to successfully block T cell exhaustion. This led to the idea that epigenetic programs could limit T-cell proliferation during immune checkpoint blockade.

Moving into the human setting, investigators then tried to take these concepts to predict the developmental state of T cell exhaustion. They chose naïve and memory CD8 T cells from healthy donors, donors with HIV, and donors with type 1 diabetes. Using these data, they created a novel bioinformatic tool to analyze a novel immunotherapy. This tool, called the Multipotency Index, is able to predict where a cell sits based on the developmental spectrum.

Using this tool, investigators analyzed whether epigenetic programs regulate human T cell exhaustion and whether epigenetic-based strategies can be used to enhance T cell-based therapies. The team knocked out DNMT3A using CRISPR and found that it significantly enhanced T cell survival during prolonged antigen exposure. Notably, Youngblood added that if the antigen is taken away, the CAR T cells undergo contraction.

Another study investigated whether this preserves the capacity of the cells to maintain an anti-tumor response in mouse models. Based on these findings, Youngblood said wild-type CAR T cells were not very effective, whereas DNMT3A knockout cells had superior tumor control in non-hematologic models. Control of the tumor in mice was also associated with persistence of CAR T cells.

Finally, Youngblood said that DNMT3A deletion in CD19 CAR T cells preserves recall potential. In retreatment, mice receiving DNMT3A knockout CAR T-cell therapy were able to rapidly control the tumor, although this protection was antigen-mediated.

All these findings could help develop approaches to preserve and maximize the effects of CAR T cells, according to Youngblood. The discoveries are also being applied toward new or modified therapies focused on improving the reprogramming abilities rather than just blockers.

Another related area of interest is TET2 knockout, which has shown potential as a blocker. When looking at survival rates among cancer patients with T cell multipotency mutations when treated with immune checkpoint blockade, Youngblood said the ASXL1 mutation in T cell and myeloid cells showed significantly better overall survival rates, and ASXL1 knockout T cells remain in a stemlike state.

“CD8 T cells are the killing force behind checkpoint blockade…they’re the ones that are doing the killing of the tumor,” Youngblood said in an interview with Pharmacy Times. “Finding that point before it turns off the killing capacity is crucial.”


Youngblood, B. Epigenetic programs regulating CD8 T cell responses during immunotherapy. Presented at: International Cancer Immunotherapy Conference. September 28, 2022.

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