Deletion of a key gene may regenerate immune cells to fight hard tumors

By deleting a single gene it can turn immune cells into cells called CD8s⁺ T cells return to regenerated soldiers that can continue to fight malignant tumors, a new study led by UT Southwestern researchers suggests. The findings, published online this week in the Journal for Cancer Immunotherapy, they could offer a new way to use the body ‘s immune system to attack cancers.

In 2017, the Food and Drug Administration approved treatments that included T-cell antigen receptor cells (CAR-T), which are made up of immune cells called T cells that have been engineered to identify specific proteins on the surface of cancer cells. When these cells are delivered by infusion, they trigger a targeted immune response against cancer cells.

CAR-T cells have been used successfully to treat cancers such as leukemia and lymphoma, often with remarkable results, says Venuprasad Poojary, Ph.D., a professor of internal medicine and immunology at UTSW. However, these treatments against hard tumors, such as those that develop in the colon, breast and lung, have not been successful.

When CAR-T cells enter these hard tumors, Poojary explains, they quickly become malignant and lose their cancer-fighting abilities. This state, known as “disruption,” is accompanied by the ingestion of proteins, the deposition of PD1 and Tim3 on their supernatants and the inability to produce their normal immune molecules. result, such as Interferon-gamma and tumor necrosis factor. Finding a way to prevent the breakdown of CAR-T cells has become an important goal in cancer research, Poojary adds.

To this end, he and his colleagues undertook published research comparing gene activity in working and tired T cells. The researchers quickly interrogated a gene called Cbl-b, which are more active, or controlled, in suppressed cells.

Poojary and his colleagues confirmed that Cbl-b activated in T cells that introduced tumors in a mouse model of colon cancer. Not only did these cells lose their tumor-fighting abilities, but they also developed a character set of cell surface proteins and an inability to secrete, or secrete, immune molecules that like harassment. However, when the scientists used the CRISPR gene editing tool for deletion Cbl-b in these cells, they regained their cancer-fighting ability and lost other suppressing properties.

Adding evidence Cbl-ba key role in T cell disruption, the researchers used genetically modified mice in which this gene was blocked. When they injected cancer cells into these animals, the tumor cells became much smaller than in active mouse cancer cells Cbl-b.

Further tests showed that it had been removed Cbl-b also inhibits inflammation specifically in CAR-T cells, Poojary adds. When he and his team removed this gene from CAR-T cells that were engineered to recognize carcinoembryonic antigen, a cell surface protein usually surpassing colon cancer, the cells were effectively fighting cancer in mice with these tumors — significantly extending their survival. However, CAR-T cells are activated Cbl-b it quickly became useless, exerting very little anti-tumor effect in animal models.

Poojary and his colleagues are working to understand the molecular mechanisms behind how Cbl-b causing T cell proliferation. Once researchers better understand this method, he notes, the use of CAR-T cells to effectively treat strong tumors may be as simple as genetically engineered without them Cbl-b.

Our study is a major step forward in the development of CAR-T cells to fight hard tumors. This could overcome the limitations of some conventional immunotherapy strategies for cancer. “

Venuprasad Poojary, Ph.D., Associate Professor of Internal Medicine and Psychiatry, UTSW