Epigenetic Inflexibility Limits Cancer PD-1 Checkpoint Inhibitor Immunotherapies

Stability of exhausted T cells in mice effects the durability of reinvigoration by PD-1 blockade.

Using a PD-L1 blockade to reinvigorate exhausted T cells in mice caused fewer T memory cells to develop, according to a study published in Science.

When the blockade was over, the reinvigorated T cells were found to become re-exhausted if antigen from the virus remained high, but did not become memory T cells when the virus was cleared.

The results of the study revealed that exhausted T cells need an epigenetic profile distinct from effector or memory T cells. The 2 cell types can mount effective immune responses to viruses and tumors, according to the study; however, the exhausted T cells fail and the memory T cells have long-lasting and durable effects.

“What these new findings on exhausted T cells tells us is that the unique epigenetic profile of exhausted T cells causes these cells to express a different overall set of genes compared to memory or effector T cells,” said researcher John E. Wherry, PhD.

Epigenetics profiles are stable and provide long-term identity to a cell. In the recent study findings, however, the epigenetic pattern only changed minimally after the PD-L1 blockade. This results in exhausted T cells being unable to change into the effector or memory cell types.

“We were surprised that the exhausted T cell epigenetic profile was not reprogrammed,” Wherry said. “Instead, the benefit we see after PD-1 pathway blockade is caused by only transient changes in gene expression that is not durable, rather than permanent epigenetic reprogramming.”

The findings suggest that the exhausted T cells are a distinct lineage of T cells, in and of themselves, rather than just being effector or memory T cells restrained by checkpoint pathways, according to the researchers.

“We predicted that exhausted T cells would not have a distinct epigenetic profile but have the molecular flexibility to obtain immune memory,” Wherry said. “But we found that exhausted T cells are quite set in their ways.”

Although cancer patients will initially respond well to PD-1 blockades, the response is not sustained. The study’s findings show that the exhausted T cells don’t maintain a durable switch to an effector T cell profile. However, in the clinic, the checkpoint inhibitors are well-tolerated and have generally manageable side effects.

“We think this shows that epigenetic fate inflexibility may limit current immunotherapies based on PD-1 checkpoint inhibitors,” said first study author Kristen Pauken, PhD.

The lack of durability clinically is not well-categorized, but the results suggest that this is partially due to the lack of sustained or permanent reprogramming of exhausted T cells.

The end goal for researchers is to specifically understand the mechanisms of checkpoint blockade effectiveness. They also hope to bring more patients sustainable immunotherapies that perhaps could use epigenetic drugs in combination with checkpoint blockade to allow epigenetic reprogramming of exhausted T cells into both functional and durable memory T cells.