Immunotherapies treat cancer by speeding up the death of tumor cells, and autoimmune diseases — in which the immune system attacks its own cells — by inhibiting those reactions. In a study of the immune system of mice, scientists at Johns Hopkins Medicine say they have discovered a new role for a protein, QRICH1, that could become a target for drugs that increase or decrease the activation of T cells to fight cancer and autoimmune diseases. The research is designed to advance the development of immunotherapies that harness the power of the immune system to fight disease. The new research findings, funded by the National Institutes of Health (NIH), were published in Science Immunology.
The QRICH1 protein is a newly identified component of a signaling pathway for CD8+ cells, the T cells that are the immune system’s killing machinery. The scientists say their experiments show that QRICH1 acts as a partial brake on the T cell response, suggesting that drugs could be designed to control the protein’s activity. In some cancers, QRICH1 may be used to increase T-cell activation to fight and destroy tumor cells more effectively. In autoimmune diseases and some blood cancers, including leukemia and lymphoma, where overactivation of T cells contributes to worsening of the disease, QRICH1 may slow down their activation. And there are potential molecular mechanisms at play, too.
In a recent study published by researchers at Nanjing Medical University, scientists found that QRICH1 suppresses pediatric T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting the protein Grp78. This endoplasmic reticulum (ER) resident protein is required for the proper folding of newly synthesized proteins. The production of unfolded or misfolded proteins during protein processing in the ER leads to ER stress, in which cells restore homeostasis by initiating downstream unfolded protein responses (UPRs). This last response occurs with the coordination of the three proteins IRE1alpha-PERK-ATF6, which bind to Grp78 when everything is in order. In case of ER stress, Grp78 detaches from the complex which thus becomes active.
A UPR stress can be adaptive or terminal. The adaptive UPR induced by a moderate ERS promotes cell survival by reducing the abnormal protein load. In contrast, the terminal UPR predominates in high-concentration or persistent ERS and causes cell death. And that is what clinicians want to encourage in the case of cancer treatment, by stressing tumor cells to the point of death. Overproduction of QRICH1 significantly downregulated GRP78 and upregulated CHOP (a stress response protein) thereby activating the terminal UPR. For the new study, the scientists first genetically engineered mice lacking the QRICH1 protein and performed experiments showing that the protein is necessary for CD8+ T cell signaling.
To do this, they extracted T cells from genetically engineered mice lacking QRICH1 and placed them in a culture dish with a signal that mimics that of a tumor cell or a cell infected by a virus. In cells lacking QRICH1, the scientists say they observed increased T cell activity in response to the infected cell, compared to T cells from mice with intact QRICH1. This increased activity indicates that QRICH1 acts as one of the brakes that slows T cell activation and limits the ability of T cells to kill infected cells. The researchers also identified a mechanism underlying this phenomenon: QRICH1 acts as a regulator of CARD11 signaling, which mediates an intracellular checkpoint for CD8+ T cell activation.
In addition to NF-kB, CARD11 combines the TCR signal to stress kinases (JNK), inducible protein synthesis (mTOR and c-Akt), and the transcription factor NF-κB. QRICH1 associates with CARD11 after TCR activation and downregulates its signaling to NF-kB, thereby affecting the inflammatory response. The researchers also looked at how T cells would respond to a natural infection. In mice infected with Listeria monocytogenes, the researchers found that mice lacking QRICH1 had a stronger immune response. In the future, the scientists plan to examine how T cells genetically engineered to lack the QRICH1 protein in mice respond to cancer cells.
- edited by Dr. Gianfrancesco Cormaci, PhD, Specialist in Clinical Biochemistry.
Scientific references
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