Cell: Inhibition of ID3 or SOX4 can reverse T cell exhaustion

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Cell: Inhibition of ID3 or SOX4 can reverse T cell exhaustion

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Cell: Inhibition of ID3 or SOX4 can reverse T cell exhaustion, which is expected to make CAR-T cells more efficient against solid tumors.

Specially engineered immune cells called CAR-T cells have proven to be powerful weapons against blood cancers, but they are far less effective against solid tumors, in part because of a process called T-cell exhaustion.

Now, in a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania have elucidated key molecular details of T cell exhaustion, pointing to specific strategies for overcoming this process.

Relevant research results were published online in the journal Cell on December 2, 2021, with the title of “An NK-like CAR T cell transition in CAR T cell dysfunction”.

The authors developed a laboratory dish model that allowed them to comprehensively study the exhaustion process of CAR-T cells used to attack pancreatic tumors.

They observed that the T cell exhaustion process in this model was very similar to that seen in patients’ T cells.

The model also revealed novel aspects of the T-cell exhaustion process, including the role of two regulators of T-cell exhaustion, ID3 and SOX4. Silencing ID3 and SOX4 allowed CAR-T cells to retain most of their effectiveness against tumor cells.

“This brings us one step closer to the next generation of CAR-T cell therapy, which will be effective against solid cancers,” said Carl June, Ph. The effect will be greater.”

CAR-T cells are natural immune cells that fight infection and cancer. To make CAR-T cells, T cells need to be extracted from a patient’s blood and genetically reprogrammed.

This reprogramming changes the patient’s T cells to express a specific chimeric antigen receptor (CAR), which allows them to recognize a marker (antigen) on the surface of the patient’s cancer cells. Then, using cell culture techniques, these reprogrammed T cells (CAR-T cells) are allowed to proliferate in vitro, and they are finally injected into the patient to attack the cancer.

Since 2017, the CAR-T cell technology June helped pioneer has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain lymphomas and leukemias — in many cases, even when these cancers are at an advanced stage. They have also been cured.

Image via Cell, 2021, doi:10.1016/j.cell.2021.11.016.

CAR-T cells have not been as effective against cancers that form solid tumors because of an important quirk of T cells called T-cell exhaustion, which is thought to be an evolutionary way to prevent these powerful immune Cells cause too much collateral damage to the body. Exhaustion is triggered when T cells are exposed to their target antigens for too long (on the order of weeks), as they often do in the case of solid tumors.

In the new study, the authors developed a lab-dish model of T-cell exhaustion to study it more closely and hope to discover ways to reverse it. They engineered CAR-T cells that target a cellular marker called mesothelin, and exposed these T cells around pancreatic tumor cells that express mesothelin, which is found in the pancreas and other found on the surface of some tumors.

After 4 weeks, the CAR-T cells responded with typical signs of exhaustion, but also with signs not seen in previous studies. These new exhaustions include changes in the identity of some T cells, such as their partial reversion to an immune cell type known as natural killer cells (NK cells), which are considered a distant relative of T cells. The authors found signs of this same T-cell-to-NK-cell transition in exhausted CAR-T cells from cancer patients.

Perhaps most importantly, the authors observed that CAR-T cell exhaustion was accompanied by a surge in the levels of two proteins, ID3 and SOX4, which act as master switches for a large number of genes in immune cells. Silencing these two apparent T-cell exhaustion switches enabled exhausted CAR-T cells to retain most of their tumor-killing ability even after prolonged exposure to tumor cells.

Thus, the new study points to a specific strategy — inhibition of ID3 and/or SOX4 — that may help CAR-T cells work better against solid tumors.

“These findings are exciting because of their potential clinical implications and because they essentially validate our new The utility of cell-based models in exploring CAR-T cell biology and continually improving this immunotherapy for the benefit of patients.”

Reference:
Charly R. Good et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell, 2021, doi:10.1016/j.cell.2021.11.016.

Cell: Inhibition of ID3 or SOX4 can reverse T cell exhaustion

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