CAR T-cell therapy, which is specifically designed to target cancer cells, has ushered in a new era in the treatment of human cancers, especially hematological malignancies. But all too often they show a troubling characteristic derived from the immune system’s own cells: a sharp decline in cancer-fighting inflammation known as “exhaustion.” Exhaustion is common in viral infections such as those caused by the human immunodeficiency virus (HIV), hepatitis B and C viruses (HBV, HCV) and COVID-19 (SARS-CoV-2).
The onset of lethargy reduced the effectiveness of CAR T-cell therapy in some patients, leading researchers to search for its cause. In a recent study, researchers from the Dana-Farber Cancer Institute and NYU Grossman School of Medicine demonstrated the critical role that mSWI/SNF (or BAF) complexes, a specialized group of proteins found in the nuclei of our cells, play in activation. T cells in fighting cancer and inducing exhaustion.
CRISPR or targeted drugs:
The discovery, reported online today in the journal Molecular Cell , suggests that targeting some of these complexes, either with gene-cutting technologies such as CRISPR or targeted drugs, could reduce exhaustion and provide CAR T cells (and generally all tumor-fighting against T cells) ability to take over cancer.
“CAR T cells and other therapies made from living cells have enormous potential in the treatment of cancer and a number of other diseases,” says lead study author Cigall Kadoch, PhD, of Dana-Farber and the Broad Institute of MIT and Harvard.
CAR (chimeric antigen receptor) T cells are created by collecting thousands of T cells from the patient’s immune system and equipping them with genes that help them attach to and destroy cancer cells. After the modified cells multiply into the millions, they are injected back into the patient where they encounter cancer cells.
The problem is that most engineered T cells, like CAR T cells, hide it’s activated just like normal T cells in body, when they encounter an infected or diseased cell, but they quickly stop multiplying and do not attack.
why: what are the determinants of T cell exhaustion?
Research over the years has suggested that exhaustion (as well as the activation and acquisition of memory-like properties) is not controlled by a single gene or a few genes, but by the coordination of many genes that together create a “program” for exhaustion. cell.
Kadoch and her colleagues began targeting mSWI/SNF complexes as potential regulators of these programs years ago. These complexes, the focus of Kadoch’s lab, are large molecular machines that slide across the genome like cursors across a line of text. Where they stop, they can open the DNA strands, turning on the genes in that region, and where they disappear, the DNA closes and turns those genes off.
Such complexes qualify as a kind of master switch that could potentially control the depletion program. Kadoch and her team set out to track their patterns throughout the course of T cell activation and exhaustion: to determine where they are on the genome of battle-ready T cells and how those positions change as exhaustion occurs.
“We have made the most comprehensive profile to date of the occupancy of these complexes in T cells over time, in both mouse and human contexts,” notes Kadoch. “We found that they move in a state-specific way, which begs the question of why they move; how do they know where to go in each state?’
It turned out that certain transcription factors, proteins crucial to the activation of highly specific sets of genes, had the greatest influence on their location. Factors guide mSWI/SNF complexes and direct them to precise locations in the genome.
“At each stage of T cell activation and exhaustion, a different constellation of transcription factors appears to guide these complexes to specific sites on the DNA,” says Kadoch.
While this profiling work was underway, co-author Iannis Aifantis, PhD, and colleagues at the NYU Grossman School of Medicine systematically turned off genes in T cells to see which ones, when silenced, slowed or stopped the exhaustion process.
“We found that all the best hits in our screen—the genes whose inhibition had the greatest impact on exhaustion—encoded the very mSWI/SNF complexes central to the Cigall lab,” Aifantis describes. “Our labs then jointly performed a detailed series of joint experiments that showed that if you suppress the genes encoding the various components of these complexes, the T cells not only don’t get exhausted, they proliferate even more than before.”
Two laboratories have followed up on these findings by using a group of newly developed small molecule inhibitors and degraders targeting mSWI/SNF complexes. They found that in response to these inhibitors, genes that promote cell exhaustion became less active, while those that promoted activation became more active. “With these inhibitors, we essentially reversed the exhaustion program,” he says, “and the resulting cells resembled more of the memory and activated features of T cells.”
The findings are particularly 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. Experiments in animal models of melanoma, acute myeloid leukemia, and other settings suggest that such compounds hold promise. In addition to beneficial changes in T cells, when groups treated animals with CAR T cells that were exposed to mSWI/SNF inhibitors, tumor growth was reduced.
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