QRICH1 Protein Found to Control T Cell Activation in Cancer and Autoimmune Diseases

In a study of the immune systems of mice, scientists at Johns Hopkins Medicine say they have found a new role for a protein, QRICH1, which could become a target for drugs to dial up or down the activation of T cells to fight cancers and autoimmune diseases.

The research was designed to advance development of immunotherapies that harness the power of the body's immune system to fight disease. Immunotherapies treat cancer by speeding up tumor cell death, and treat autoimmune disorders - in which the body's immune system attacks its own cells - by tamping down such reactions.

Finding new targets for future drugs that could fine-tune these treatments, making them safer and more effective, is a promising avenue of research."

Joel Pomerantz, Ph.D., senior author, associate professor of biological chemistry at the Johns Hopkins University School of Medicine

The new research findings, supported by funding from the National Institutes of Health, were published March 14 in Science Immunology. 

The protein QRICH1 is a recently identified component of a signaling pathway of CD8+ cells, which are T cells that make up the killing machinery of the immune system, says Pomerantz. The scientists say their experiments show that QRICH1 acts as a partial brake that regulates T-cell response, indicating that drugs could be designed to control the protein's activity.

In certain cancers, QRICH1 could be used to increase T-cell activation to fight and kill off cancer cells more effectively. In autoimmune diseases and certain blood cancers, including leukemia and lymphoma, in which overactivation of T cells contributes to worsening of disease, QRICH1 could slow down the activation of T cells, Pomerantz says.

For the new study, the scientists first genetically engineered mice to lack the QRICH1 protein, and conducted experiments demonstrating that the protein is necessary to the CD8+ T cell signaling pathway.

To do so, the scientists extracted T cells from mice genetically engineered to lack QRICH1 and placed the immune cells in a culture dish with a signal that mimics a cancer cell or a virally infected cell.

In cells lacking QRICH1, the scientists say they observed an uptick in T-cell activity in response to the infected cell when compared with T cells from mice with intact QRICH1. The scientists say this increased activity indicated that QRICH1 serves as one of the brakes that slows down T-cell activation and limits T cells' ability to kill infected cells.

The researchers further examined how T cells would respond to a naturally occurring infection. In mice infected with listeria monocytogenes, a bacterium that contaminates food, the researchers found that mice lacking QRICH1 had a stronger immune response.

 "T cells genetically engineered to lack QRICH1 become more activated even in response to a natural infection with a bacterial organism," Pomerantz says.

Next, Pomerantz says the researchers intend to examine how T cells genetically engineered to lack the QRICH1 protein in mice respond to cancer cells.

The investigators say their work offers insights into "promising new molecular machinery that controls immune cell activation, and if we can understand it and find drugs to target it, we could enhance immune function for therapeutic purposes, including cancer," he says.

Funding support for this research was provided by the National Institutes of Health (RO1AI43053, F31CA254167 and T32GM007445).

In addition to Pomerantz, other Johns Hopkins researchers who contributed to this study are Nicole Carter, Wihib Hankore, Yong-Kang Yang, Chao Yang, Shelby Hutcherson, Wyatt Fales, Anushka Ghosh, Piyusha Mongia, Sophie Mackinnon, Anna Brennan and Robert Leone.