CAR-T cell therapy has had success in treating children and adults with leukemia and lymphoma. However, CAR T cells have not had the same success against solid tumors, with problems involving persistence and function. Now, St. Jude Children’s Research Hospital scientists report they have uncovered a molecular mechanism that in a preclinical study unlocked the promise of CAR-T cell therapy for treatment of solid tumors.
Their findings were published in the journal Nature in a paper titled, “cBAF complex components and MYC cooperate early in CD8+ T cell fate.”
“The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anticancer immunotherapy,” wrote the researchers. “Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF).”
“Our work extends from the basic biology of T lymphocytes to a possible application in the clinic, with an exploration of deep molecular mechanisms along the way,” said co-corresponding author Doug Green, PhD, chair, St. Jude department of immunology. “We found that just like many of us, if you are an activated T cell, things that happen early in your life can impact your later development. We identified that an interaction between the protein c-Myc and the complex cBAF early in T-cell activation influences cell fate trajectory.”
“Effector cells do a job and then die,” Green explained. “Memory cells stick around and can generate effector cells (while maintaining the memory cell pool) and therefore they can launch continued attacks. So, we think that memory cells likely do a better job of getting rid of tumors.”
Green’s team recently showed that the distribution of the protein c-Myc in a parental T cell can be important for this process. Researchers knew that a daughter cell with more c-Myc becomes an effector cell. In this study, the team found that the protein complex cBAF (canonical Brg1/Brg-associated factor) interacted with c-Myc. Daughter cells with high cBAF and c-Myc concentrations became effector T cells.
Co-corresponding author Hongbo Chi, PhD, St. Jude department of immunology, studied 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 collaborated to confirm that targeting multiple parts of the cBAF complex affects memory T-cell generation. The researchers discovered the exact locations in the genome where cBAF components bind and found that cBAF promoted the expression of genes associated with effector cell function.
The team of researchers 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.
“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.”
