Molecular Immune Brake Identified

The immune system requires careful regulation. When it reacts too strongly, it can cause damaging inflammation in otherwise healthy tissue; and when it doesn’t react strongly enough, it can let infections and tumor cells escape detection.

In recent years, researchers have discovered several molecules that act as natural immune brakes. These discoveries have opened the door to immunotherapy—a way to potentially leverage the immune system to attack cancer cells. For immunotherapy to reach its full potential in human patients, however, more must be learned about factors driving cancer immunity.

In a study published today in EMBO Reports, researchers show that a molecule called EGR4—known mainly for its role in male fertility—serves as a critical brake on immune activation. According to the study, taking EGR4 away promotes the activation of so-called killer T cells, which infiltrate and attack tumors and thereby boost anticancer immunity.

“Other early growth response proteins, or EGRs, are important to T cell activity, but whether EGR4 also has a role in immunity has been largely overlooked,” says senior author Jonathan Soboloff of LKSOM. “Our study reveals a new side to the importance of EGR4.”

In initial experiments, the researchers found that T cell activation is associated with EGR4 upregulation. They then showed that knocking out EGR4 from immune cells results in a dramatic increase in calcium signaling and expansion of T helper type 1 (Th1) cell populations. Th1 cells activate killer T cells in response to the presence of foreign entities or tumor cells, and then killer T cells wipe out the invader.

The researchers next studied the functional importance of EGR4 in cancer immunity by utilizing an adoptive mouse model of melanoma in which some host animals lacked EGR4 expression. Compared to mice with typical EGR4 levels, EGR4 knockout animals showed evidence of expanded populations of Th1 cells and enhanced anticancer immunity. In particular, EGR4 knockout mice had reduced lung tumor burden and fewer metastases than mice with normal EGR4 expression.

In future work, the researchers plans to further explore strategies for EGR4 targeting. The development of an agent to target EGR4 specifically may be difficult, due to the diverse actions of EGR pathways. “But eliminating EGR4 specifically from a patient’s T cells, and then putting those cells back into the patient, may be a viable immunotherapeutic approach,” says coauthor Dietmar Kappes of the Fox Chase Cancer Center.