This image shows killer T cells surrounding and attacking a cancer cell. A new atlas developed by researchers at UC San Diego could make it possible to design custom T cells for immunotherapy to maximize patient benefit while minimizing potential negative effects.
Image Credit: National Institutes of Health/NIAID
Scientific Frontline: "At a Glance" Summary
- Main Discovery: A comprehensive genetic atlas of CD8+ T cell states was developed, identifying specific transcription factors that determine whether these immune cells persist as effective defenders or succumb to dysfunctional exhaustion.
- Methodology: Researchers utilized advanced computational modeling, gene editing, and in vivo mouse studies to map nine distinct T cell states and experimentally manipulated genetic switches to decouple the pathways regulating immune memory from those driving exhaustion.
- Key Data: The study identified nine distinct CD8+ T cell states and discovered two previously unknown transcription factors, ZSCAN20 and JDP2, which, when inhibited, restored tumor-killing capacity without sacrificing long-term immune memory.
- Significance: This research fundamentally challenges the long-standing scientific belief that T cell exhaustion is an inevitable byproduct of chronic immune activation, proving instead that exhaustion and protective memory are distinct, separable genetic programs.
- Future Application: These findings provide a blueprint for engineering "custom" T cells in adoptive cell transfer and CAR T-cell therapies that are programmed to resist burnout while maintaining long-term potency against cancer and chronic infections.
- Branch of Science: Immunology, Oncology, and Computational Biology.
A multi-institution study led by researchers at University of California San Diego, the Salk Institute for Biological Studies and the University of North Carolina at Chapel Hill has mapped the internal genetic programs that determine the behavior of powerful white blood cells, called CD8 killer T cells, which are critical for controlling infections and fighting cancer. These cells take on different states depending on their environment, and these cell states can determine how well cancers respond to immunotherapy. Understanding how different cell states arise could help make these treatments more effective and targeted. The findings are published in Nature.
“This study shows that we can begin to precisely manipulate immune cell fates and unlock new possibilities for enhancing immune therapies,” said co-corresponding author Wei Wang, PhD, a professor in the Departments of Cellular and Molecular Medicine and Biochemistry and Molecular Biophysics at UC San Diego. Additional co-corresponding authors on the study include Susan M. Kaech, PhD, at the Salk Institute, and H. Kay Chung, PhD, at UNC Lineberger Comprehensive Cancer Center.
Because protective and dysfunctional CD8 T cell states can look very similar, we designed this study to ask whether protective immune memory and dysfunction could be genetically separated. Wwe flipped specific genetic switches in the T cells to see if we could restore their tumor-killing function without damaging their ability to provide long-term immune protection,” said Chung. “We found that it was indeed possible to separate these two outcomes.”
The role of CD8 killer T cells is to seek out and destroy virus-infected cells and cancer cells. During chronic viral infections or within tumors, CD8 T cells can gradually lose their killing ability and enter a state known as T cell exhaustion, in which they become dysfunctional and ineffective. Using advanced lab, gene, mouse and computational approaches, the researchers analyzed nine distinct CD8 T cell states that spanned a spectrum from protective to dysfunctional.
“This is a challenging task”, said Wang. “Because genes work together in complex regulatory networks that are difficult to decipher, powerful computational tools are essential to pinpoint which regulators drive specific cell states.”
The researchers identified specific transcription factors — proteins that control gene activity — that act like switches to direct killer T cells into different functional states. Specifically, they discovered new exhausted-state transcription factors (ZSCAN20 and JDP2) that had no known prior function in T cells. When these factors were turned off, exhausted T cells regained their ability to kill tumors without losing their capacity for long-term immune memory.
“Once we had this map, we could start giving T cells much clearer instructions — helping them keep the traits that allow them to fight cancer or infection over the long term, while avoiding the pathways that cause them to burn out,” Kaech said.
The researchers will next use advanced laboratory techniques and AI‑guided computational modeling to develop precise genetic “recipes” for programming killer T cells—directing them toward beneficial, long-lasting states while actively avoiding dysfunctional ones. This level of precision is essential for advancing therapeutic approaches where immune cells are modified and returned to patients, such as adoptive cell transfer therapy, which involves expanding a patient’s own tumor‑fighting T cells outside the body and reinfusing them to boost their ability to attack cancer, and chimeric antigen receptor therapy, which engineers T cells with synthetic receptors that help them recognize and kill cancer cells more effectively.
“It is important to emphasize that this work was truly a team effort,” Chung said. “It began with the synergy between Dr. Kaech’s immunology lab at Salk and Dr. Wang’s computational platform at UC San Diego, and after my move to UNC, collaborations here allowed us to strengthen and extend the findings.”
Disclosures: Susan M. Kaech is an SAB member for Pfizer, EvolveImmune Therapeutics, Arvinas and Affini-T, advisor for Barer Institute of Raphael Holdings and academic editor at Journal of Experimental Medicine. The remaining authors declare no conflict of interest.
Published in journal: Nature
Title: Atlas-guided discovery of transcription factors for T cell programming
Authors: H. Kay Chung, Cong Liu, Anamika Battu, Alexander N. Jambor, Brandon M. Pratt, Fucong Xie, Brian P. Riesenberg, Eduardo Casillas, Ming Sun, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J. Brown, Matthew Smith, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Z. Audrey Wang, Jun Wang, Bryan Mcdonald, Peixiang He, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael LaPorte, Thomas H. Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, Jennifer Modliszewski, April Williams, Yusha Liu, Zhen Wang, Jieyuan Liu, Yiming Gao, Zhiting Hu, Ukrae H. Cho, Longwei Liu, Yingxiao Wang, Diana C. Hargreaves, Gianpietro Dotti, Barbara Savoldo, Jessica E. Thaxton, J. Justin Milner, Susan M. Kaech, and Wei Wang
Source/Credit: University of California, San Diego | Miles Martin
Reference Number: imgy020426_01
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