A fortuitous finding and collaboration
While Dr. Green's group was studying T cell divisions, co-corresponding author Hongbo Chi, Ph.D., St. Jude Department of Immunology, was studying how a T cell becomes a memory cell. Chi's laboratory used the genetic screening tool CRISPR to knockout genes and observe the impact on T-cell fate.
"T cells represent a cornerstone for cancer immunotherapy," Chi said. "There is a continuing interest in improving T-cell function for better cancer treatment. As such, my lab is interested in identifying metabolic drivers in T-cell memory responses. Given the crosstalk between metabolic and epigenetic pathways, we did an in vivo CRISPR screen of epigenetic regulators of T-cell memory. That led us to cBAF."
"We were looking at what happens to components of the cBAF complex in activated T cells," Green said. "At the same time, the Chi lab had been fishing in a pond filled with molecules that might influence the cell fate to generate effector versus memory T cells. When we compared notes, we realized that our independent findings were telling us something interesting, so we joined forces."
The groups worked together to confirm that targeting multiple parts of the cBAF complex affects memory T-cell generation. The researchers also found the exact locations in the genome where cBAF components bind and found that cBAF promoted the expression of genes associated with effector cell function.
Together against tumors
The collaborators used the molecular information they discovered to increase CAR T-cell efficacy. They applied a cBAF inhibitor during CAR T-cell activation to generate more memory T cells. In a preclinical model, the inhibitor-treated T cells controlled tumor growth better than untreated cells. The treated cells also survived longer and in larger numbers. The researchers replicated the promising results in multiple solid tumor types. The study is one of the first to show that CAR T cells can be modified transiently to more effectively kill solid tumors.
"cBAF factors are a potential target to boost CAR-T therapeutic effects against cancer," Chi said, "but our work also demonstrates that by better understanding basic immunobiology and T cell function, we can develop better therapeutics for cancer and other diseases."
Authors and funding
The study's first authors are Ao Guo, of St. Jude, and Hongling Huang, formerly of St. Jude. The study's other authors are Zhexin Zhu, Mark J. Chen, Hao Shi, Sujing Yuan, Piyush Sharma, Jon P. Connelly, Swantje Liedmann, Yogesh Dhungana, Zhenrui Li, Dalia Haydar, Mao Yang, Helen Beere, Christopher DeRenzo, Shondra M. Pruett-Miller, Jeremy Chase Crawford, Giedre Krenciute and Charles W.M. Roberts,all of St. Jude; and Jason T. Yustein, Baylor College of Medicine.
The study was supported by grants from by the National Institutes of Health (AI123322, CA231620 and CA253188); the National Cancer Institute (K99CA256262 and P30CA021765); and ALSAC, the fundraising and awareness organization of St. Jude.
Read the full text of the Nature article:
cBAF complex components and c-Myc cooperate early in CD8+ T cell fate
Nature, published June 22, 2022
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