What is the key source of T cell exhaustion?

 A discovery in the US paves the way for drugs that could prevent T-cell therapy from losing its effectiveness over time.

Researchers from the Dana-Farber Cancer Institute and the Grossman School of Medicine at New York University (NYU) in the United States have identified the dominant role of a specialized group of proteins in the nuclei of our cells, called mSWI/SNF (or BAF), both by activating T cells to attack cancer and by inducing fatigue.

CAR-Tcell therapies have opened a new era in the treatment of human cancers, particularly hematologic cancers. However, they often exhibit a frustrating trait inherited by the body's immune system cells: "tiredness." Exhaustion not only occurs in cancer T cells but is also commonly associated with viral infections.

The results, reported in Molecular Cell, suggest that targeting these complexes, either with gene-cleavage techniques such as CRISPR or with targeted drugs, can reduce fatigue and confer cancer-fighting potential on CAR-T cells.

 Sigal Kadosh of the Dana-Farber and Broad Institute of the Massachusetts Institute of Technology and Harvard University.

 "When they encounter infected or diseased cells, they become activated, but then quickly stop multiplying and no longer attack.

 We and other groups wanted to understand why: What is the determinant of T cell deficiency? Research shows that hunger exists.

" It's not controlled by one or more genes. genes, but through the coordination of many genes that together make up the "program" of cell starvation.

 Many years ago, researchers began to see the mSWI/SNF complex as a potential regulator of these programs, and these complexes are considered to be a kind of master switch that controls the fatigue program. 

The team set out to track the patterns of T cell activation and destruction: determining where fighter T cells are located on the genome and how those positions change with atrophy.

During the test work, the NYU Grossman School of Medicine team systematically silenced T-cell genes to see which, when silenced, slowed or stopped the fatigue process.

"Our researchers then performed a detailed series of collaborative studies that showed that if you turn off the genes that encode the various components of these complexes, the T cells not only go out but also proliferate more than before.

" explained co-author Iannis Aifantis. "We basically reversed the degradation program with these inhibitors," he said, "and the resulting cells looked more like active shape-memory T cells.

"The results come especially timely as the first compounds that specifically inhibit the catalytic activity of mSWI/SNF complexes are currently being tested in phase 1 cancer studies.

“Our labs are excited by these results in many ways, from discovering another important example of a diverse repertoire of mSWI/SNF activity in human biology to the ability to target these functions to improve treatment strategies to fight cancer treatments and other diseases, Kadoch finally said.

he drops into listlessness has impaired the effectiveness of CAR T-cell therapies in some patients, leading scientists to search for the cause. In a new study, scientists at Dana-Farber Cancer Institute and NYU Grossman School of Medicine show that a specialized group of proteins in the nuclei of our cells called mSWI/SNF (or BAF) complexes, play a critical role in both activating cancer-fighting T cells and triggering fatigue.

The discovery, reported online today in the journal Molecular Cell, suggests that targeting certain of these complexes, either through gene editing technologies such as CRISPR or through targeted drugs, could reduce exhaustion and give CAR T cells (and all tumor-fighting T cells in general) the stamina they need to fight cancer.

"CAR T cells and other therapies made from living cells have enormous potential for treating cancer and a range of other diseases," says the study's lead author, Cigall Kadoch, Ph.D., of Dana-Farber and the Broad Institute of MIT and Harvard. "However, to realize this potential, the field had been wrestling with the problem of fatigue. Our findings in this study point to new, clinically actionable ways to address this problem."

CAR-T (chimeric antigen receptor) cells are made by collecting thousands of T cells from a patient's immune system and engineering them with genes that help them attach to and destroy cancer cells. After the modified cells have multiplied millions of times, they're re-injected into the patient, where they attack the cancer cells.

"The problem is that most engineered T cells, like the CAR T cells, die back," Kadoch says. "They get activated, just like normal T cells in our body, when they encounter an infected or diseased cell, but they quickly stop multiplying and do not go on the attack. We and other groups wanted to understand why that is: what are the key factors in T cell exhaustion?"

Over the years, research has shown that exhaustion (like 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 an exhaustion "program" for the cell.

Kadoch and her colleagues began focusing on mSWI/SNF complexes as potential regulators of these programs years ago. These complexes, which are the focus of Kadoch's lab, are large molecular machines that glide across the genome like cursors on a line of text. Where they stop, they can open DNA strands and turn on genes in that region, and where they disappear, the DNA is closed and the genes in question are turned off.

Such complexes lend themselves to being a kind of master switch that could potentially control the exhaustion program. Kadoch and her team decided to track their patterns over the entire course of T-cell activation and exhaustion: They wanted to find out where they are located in the genome of battle-ready T cells and how those positions change when exhaustion sets in.

"We profiled the most comprehensive occupancy of these complexes in T cells over time to date, in both mice and humans," Kadoch explains. "We found that they move in a state-specific manner, which raises the question of why they move; how do they know where to go in each state?"

It turns out that certain transcription factors, proteins critical for activating highly specific sets of genes, have the greatest influence on their location. The factors direct the 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 direct these complexes to specific locations on the DNA," Kadoch explains.

cell

The term "cell" can refer to various things depending on the context. Here are a few possible meanings:

1. Biological Cell: In biology, a cell is the basic structural and functional unit of all living organisms. It is the smallest unit of life and contains genetic material, organelles, and a cell membrane. Cells can be classified into two major types: prokaryotic cells (lacking a nucleus) and eukaryotic cells (containing a nucleus).

2. Prison Cell: A prison cell refers to a confined space where inmates are held in correctional facilities. It is typically a small room or enclosure with limited amenities, intended to house individuals who have been convicted of crimes or are awaiting trial.

3. Battery Cell: A battery cell is a single unit within a battery that converts chemical energy into electrical energy. Multiple battery cells are combined to form a battery pack, which can be used in various applications like electronics, vehicles, and renewable energy storage.

4. Solar Cell: A solar cell, also known as a photovoltaic cell, is a device that converts sunlight directly into electrical energy using the photovoltaic effect. Solar cells are used to generate electricity from sunlight and are commonly used in solar panels to harness renewable energy.

5. Cell (Spreadsheet): In the context of computer software, a cell refers to an individual unit within a spreadsheet. Spreadsheets are used for organizing and analyzing data, and cells are used to store and manipulate individual pieces of data, such as numbers, text, or formulas.

These are just a few examples, and the term "cell" can have other meanings in different fields or contexts. If you have a specific context in mind or need more information on a particular type of cell, please provide more details.