Science publication from SCI leader finds that T cell effector programming is regulated by the Mediator kinase module
SCI leader Crystal Mackall, MD, and lead author Katie Freitas, a Stanford Immunology PhD candidate and Mackall lab member, have published an article in Science demonstrating that the Mediator kinase module is a primary regulator of T cell effector programming.
“This work is surprising because Mediator has been extensively studied in fundamental biology but has never been implicated in regulating the immune system. Given the extensive understanding of Mediator biology, this work provides a new, fertile axis for manipulation in the context of immune therapies,” stated senior author Mackall.
T cell-based immunotherapies have shown effectiveness at treating some cancers, but most patients do not achieve a durable response. T cell potency is considered a main barrier to optimal outcomes. To identify T cell fitness regulators that affect exhaustion, senescence, anergy, and immunosuppression, Dr. Mackall and colleagues used genome-wide CRISPR knock-out screens in human T cells.
“Genome-wide CRISPR screening allows us to test thousands of gene deletions in parallel,” explained Freitas. “This unbiased approach allows us to ask, ‘What genes prevent T cells from working their hardest to fight cancer?’”
Researchers identified that targeted deletion of genes MED12 (Mediator complex subunit 12) or CCNC (cyclin C), both of which encode Mediator subunits, in human CAR T cells increased proliferation, cytokine production, and increased tumor clearance. MED12 and CCNC are also required for kinase activity of the Mediator kinase module.
“When we knocked out MED12, the CAR-T cells became supercharged. They sustained their ability to kill tumor cells for a longer timeframe, keeping mice tumor-free for over 100 days,” reported Freitas.
“Surprisingly, our CRISPR screen uncovered the Mediator kinase module, a component of the Mediator complex, which is a master regulator of transcription. Disruption of the Mediator kinase module reprogrammed T cells to have enhanced anti-tumor activity.”
The findings show that the Mediator kinase module is a target for enhancing the potency of anti-tumor T cell responses and highlight the potential for gene editing technologies in cancer immunotherapy.
[Artwork: LLUM Dimensions]