Frederick A. DICK

Professor of Pathology and Oncology, Western University Distinguished Scientist, London Regional Cancer Program Scientist, Children’s Health Research Institute
Scientist, Lawson Health Research Institute, UK

EZH2 inhibition activates viral mimicry and immune mediated elimination of resting B-cells

Host: L. Banks

Viral mimicry is a mechanism of action by epigenetically directed therapeutic agents in cancer treatment. It is based on the concept that endogenous retroviral elements and other repetitive sequences are prone to misexpression in transformed cells. Therapeutic agents that trigger repeat expression produce an inflammatory response and activate cancer cell killing. EZH2 is a histone methyltransferase that deposits H3K27me2/3 in repressive heterochromatin during development and it is frequently overexpressed or mutationally activated in cancer leading to the silencing of tumor suppressor genes. EZH2’s role in repeat repression is less investigated.

We discovered that systemic administration of EZH2 inhibitors to mice stimulates inflammation and immune self-recognition of normal resting splenic B-cells. We generated a novel cytosolic pattern recognition receptor loss-of-function mouse model with mutations in Cgas, Ifih1 (Mda5), and Rig1 that we call CID. CID mutations eliminate the recognition of cytoplasmic dsRNA and dsDNA and the ability to initiate inflammation. In both WT and CID mutant B-cells, EZH2 inhibition with GSK343 induced widespread loss of H3K27me3 at repetitive elements and upregulated their expression as revealed by ChIP-seq and RNA-seq approaches. Only WT B-cells translocate NF-kB to the nucleus and activate expression of inflammatory chemokines. Furthermore, infiltration of cytotoxic T cells and neutrophils into the spleen in response to EZH2 inhibition was blocked in CID mutants preserving viability of B-cells. This study demonstrates a pharmacologically induced mechanism of inflammation that causes self-recognition and B-cell elimination. The mechanism of response to EZH2 inhibitors shares similar features with Epstein-Barr virus infected B-cells suggesting this a viral mimicry mechanism.

These findings suggest important considerations for the use of EZH2 inhibitors in scenarios where B-cell function and viability are important. Our work also suggests they may be useful for elimination of B-cells in autoimmune disorders.


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