image: In many ways, T cells are like race cars. They require fuel to do their jobs and, when active for too long, can run out of energy. New findings from Van Andel Institute scientists and collaborators found a potential treatment target to reinvigorate dysfunctional or exhausted cells. Called PTGIR, this specialized molecule regulates T cell numbers and cancer-fighting powers. Too much PTGIR slams the brakes, limiting cells’ ability to combat cancer. Medications that block PTGIR may offer new opportunities to reenergize T cells and get them back in the race.
Credit: Image by Gabrielle Eisma. Courtesy of Van Andel Institute.
GRAND RAPIDS, Mich. (June 27, 2025) — Van Andel Institute scientists and collaborators have discovered a potential treatment target that may re-energize dysfunctional or “exhausted” immune cells in their fight against cancer.
The target is an immune checkpoint called PTGIR, which regulates the number and cancer-fighting powers of T cells, the soldiers of the immune system. Too much PTGIR puts a brake on T cells and reduces their ability to release cancer-killing molecules.
The findings, published in the journal Nature Immunology, could help improve cancer immunotherapies by paving the way for new immune checkpoint inhibitors or engineered T cell therapies that block PTGIR signaling and re-invigorate T cells.
“Immunotherapies are game changers for cancer treatment, but they don’t work for everyone or for all cancers,” said Michael Dahabieh, Ph.D., the study’s first author and a postdoctoral fellow in the lab of Russell Jones, Ph.D., at VAI. “Blocking PTGIR offers another opportunity to develop more targeted treatments that help the immune system fight disease.”
Immune checkpoints are molecules that pepper the outside of T cells and some cancer cells. In immune cells, checkpoints help the immune system do its job without accidentally attacking healthy cells. In cancer, checkpoints allow malignant cells to evade immune attacks. Medications that block checkpoints, called immune checkpoint inhibitors, have become powerful tools for treating cancer.
Most known immune checkpoints rely on interactions between proteins, which can limit treatment options. The new checkpoint is based on a protein (PTGIR) and a lipid (prostacyclin), which creates new prospects for leveraging the checkpoint to fight cancer. To date, only a few similar protein-lipid interactions have been described in T cells.
Prostacyclin is found in and around tumors and contributes to T cell exhaustion by interacting with PTGIR. The amount and availability of PTGIR is regulated by another protein called NRF2. More NRF2 means more PTGIR — which results in widespread T cell exhaustion.
“The more PTGIR, the more opportunities there are for it to interact with prostacyclin,” Jones said. “This increased activity slams the brakes on T cell activity and makes it more difficult for them to continue fighting cancer cells. Shutting down this interaction offers an opportunity to bolster the immune system and treat cancer.”
Other authors include Lisa M. DeCamp, Brandon M. Oswald, Ph.D., Susan M. Kitchen-Goosen, Zhen Fu, Ph.D., Matthew Vos, Shelby E. Compton, Ph.D., Joseph Longo, Ph.D., Nicole M. Foy, Kelsey S. Williams, Ph.D., Abigail E. Ellis, Amy Johnson, Ibukunoluwa Sodiya, M.S., Michael Vincent, Ph.D., Hyoungjoo Lee, Ph.D., Ryan D. Sheldon, Ph.D., and Connie M. Krawczyk, Ph.D., of Van Andel Institute; and Chen Yao, Ph.D., and Tuoqi Wu, Ph.D., of University of Texas Southwestern Medical Center.
Research reported in this publication was supported by Van Andel Institute; Van Andel Institute Metabolism and Nutrition (MeNu) Program Pathway to Independence Awards (Dahabieh and Longo); the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award nos. DP2AI154450 (Yao) and R01AI158294 (Wu); the Cancer Prevention and Research Institute of Texas under award no. RR210035 (Yao); the National Institute on Aging of the National Institutes of Health under award no. R01AG056524 (Wu); a V Scholar Award (Wu); an American Federation for Aging Grant for Junior Faculty (Wu); a Clinic & Laboratory Integration Program Grant (Cancer Research Institute) (Wu); startup funds from University of Texas Southwestern (Yao and Wu); and startup funds from University of Colorado (Wu). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding organizations.
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Journal
Nature Immunology
Article Title
The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion
Article Publication Date
27-Jun-2025