Removing EGR4 “Brake” on Immune Activation May Be Viable I/O Therapeutic Approach

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ArcherDX said its Archer Immunoverse and VariantPlex NGS assays will be used by Ambry toward offering its biopharma customers large-scale immune repertoire analysis and chimeric antigen T-cell receptor (CAR-T) manufacturing characterization and pharmacodynamics. [royaltystockphoto/Getty Images]

Scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) and Fox Chase Cancer Center show that EGR4, known mainly for its role in male fertility, serves as a critical brake on immune activation. The new study “Suppression of Ca2+ signals by EGR4 controls Th1 differentiation and anti‐cancer immunity in vivo”, published online in EMBO Reports, demonstrates that taking EGR4 away, thus effectively releasing the brake, promotes the activation of killer T cells, which infiltrate and attack tumors and thereby boost anticancer immunity.

“While the zinc finger transcription factors EGR1, EGR2, and EGR3 are recognized as critical for T‐cell function, the role of EGR4 remains unstudied. Here, we show that EGR4 is rapidly upregulated upon TCR engagement, serving as a critical “brake” on T‐cell activation. Hence, TCR engagement of EGR4−/− T cells leads to enhanced Ca2+ responses, driving sustained NFAT activation and hyperproliferation. This causes profound increases in IFNγ production under resting and diverse polarizing conditions that could be reversed by pharmacological attenuation of Ca2+ entry,” wrote the investigators.

“Finally, an in vivo melanoma lung colonization assay reveals enhanced anti‐tumor immunity in EGR4−/− mice, attributable to Th1 bias, Treg loss, and increased CTL generation in the tumor microenvironment. Overall, these observations reveal for the first time that EGR4 is a key regulator of T‐cell differentiation and function.”

“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,” explained Jonathan Soboloff, Ph.D., professor of Medical Genetics and Molecular Biochemistry at the Fels Institute for Cancer Research and Molecular Biology at LKSOM. “Our study reveals a new side to the importance of EGR4.”

Soboloff’s team examined the influence of EGR4 expression in immune cells in collaboration with Dietmar J. Kappes, Ph.D., professor of Blood Cell Development and Cancer at Fox Chase Cancer Center. In initial experiments, the researchers found that T cell activation is associated with EGR4 upregulation. They then showed that knocking-out, or eliminating, EGR4 from immune cells results in a dramatic increase in calcium signaling and expansion of T helper type 1 (Th1) cell populations. Th1 cells, in response to the presence of foreign entities, including tumor cells, activate cytotoxic, or killer, T cells, which then wipe out the invader.

“We know from our previous work that T cells control calcium signaling and that when intracellular calcium levels are elevated, calcium signaling can drive T cell activation,” Soboloff said.

The Soboloff and Kappes labs 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 Soboloff and Kappes groups plan 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,” Kappes said.

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