Skip to main content

Study identifies critical regulator of tumor-specific T cell differentiation

Jun. 18, 2019, 10:22 AM

Immune checkpoint therapy has revolutionized cancer therapy, leading to long-term remission for patients with advanced cancer. However, most cancer patients either do not respond or have only short-term responses to checkpoint therapy, which targets inhibitory receptors on T cells.

A study published June 17 in Nature offers clues as to why blocking inhibitory receptors on tumor-infiltrating T cells may not always work. Mary Philip, MD, PhD, assistant professor of Medicine in the Division of Hematology and Oncology and a senior author on the story, together with Andrea Schietinger, PhD, of the Sloan Kettering Institute, found that the thymocyte selection-associated high-mobility group box protein, TOX, is expressed at high levels in dysfunctional tumor-infiltrating T cells in mice and humans.

The investigators found that TOX controls the high expression of inhibitory receptors such as PD1 on dysfunctional tumor-infiltrating T cells. These inhibitory receptors act like brakes on T cells. The team deleted TOX from tumor-infiltrating T cells to see if that would restore their function. To their surprise, though the tumor-infiltrating T cells no longer expressed PD1 and other inhibitory receptors, the T cells were still dysfunctional and unable to eliminate cancers. Even more surprising, the T cells without TOX were unable to survive long term. The study demonstrates that control of the killing machinery in T cells is uncoupled from regulation of inhibitory receptors.

“Taking off the brakes is not enough to restore the killing capacity of anti-tumor cells. In fact, T cells need the brakes to avoid getting over-activated and dying,” Philip said.

The study follows a previous investigation published in Nature on May 25, 2018, by Philip and colleagues on T cell dysfunction in liver cancer using mouse models. Philip was the lead author of that study.

The overarching goal of Philip’s research group is to decipher the mechanisms regulating T cell dysfunction in cancers and to design new strategies to override these mechanisms to improve cancer immunotherapy.

Recent Stories from VUMC News and Communications Publications

Vanderbilt Medicine
Hope
Momentum
VUMC Voice

more