Protein Group May Help T Cells Overcome Exhaustion

Scientists at Dana-Farber Cancer Institute and NYU Grossman School of Medicine have discovered that exhaustion in cancer-fighting T cells, including CAR T cells, is caused by a group of proteins in the nuclei of our cells called mSWI/SNF complexes. The findings, published in the journal Molecular Cell, suggest that the complexes can be targeted by gene-cutting technologies such as CRISPR or with targeted drugs to reduce exhaustion and give CAR T cells the staying power to take on cancer.

CAR T cells are made by collecting and genetically modifying thousands of an individual patient’s T cells to latch onto and destroy cancer cells. After the modified cells reproduce into the millions, they’re injected back into the patient, where they strike at cancer cells. The problem is that most engineered T cells, like CAR T cells, tend to tire quickly. They get activated, just as normal T cells in our body do when encountering an infected or diseased cell, but promptly stop proliferating and fail to go on the attack.

Over the years, researchers have suggested that this exhaustion is not controlled by a single gene, but by multiple genes coordinating to generate an exhaustion “program” for the cell. mSWI/SNF complexes, which are large molecular machines that glide along the genome, can act as a “switch” that could potentially control the exhaustion program.

For their work, the scientists tracked these patterns throughout T cell activation and exhaustion to determine where they’re situated on the T cells’ genome and how those positions change over time. They found that the biggest influences on their location were certain transcription factors, proteins critical to activating highly specific sets of genes.

The researchers discovered that all the top hits in their screen – the genes whose inhibition had the most significant impact on exhaustion – encoded the very mSWI/SNF complexes central to the study. They also found that if you stifle the genes encoding various components of these complexes, the T cells don’t get exhausted and robustly proliferate. They employed a group of newly-developed small molecule inhibitors and degraders targeting mSWI/SNF complexes and observed that, in response to these inhibitors, genes promoting cell exhaustion became less active while those spurring activation became even more active.

These findings are timely given that the first compounds that specifically inhibit the catalytic activity of mSWI/SNF complexes are now being tested in Phase 1 clinical trials for cancer. This research presents new, clinically-actionable ways of addressing exhaustion in CAR T cells and other therapies made from living cells.