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Published on: January 9, 2018
Loss of EHMT2 enhances NK cell-driven anti-tumor immunity through TGF-β1 suppression
Suresh Chava1, Suresh Bugide1, Parmanand Malvi1
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
Abstract:
Natural Killer (NK) cells play a critical role in regulating tumor growth, but our understanding of the mechanisms underlying their anti-tumor activity remains limited. We identified the histone methyltransferase EHMT2 as a key suppressor of NK cell-mediated cytotoxicity. EHMT2 inhibition in cancer cells enhanced NK cell-mediated elimination of diverse cancers, including uveal melanoma, breast cancer, and pancreatic cancer. EHMT2 loss increased AZGP1 and decreased TGF-β1 levels, resulting in the autocrine elevation of NKG2D ligands MICB and ULBP3, chemokines in cancer cells, and the paracrine stimulation of NK cell function. In a syngeneic pancreatic cancer model, EHMT2 inhibition suppressed tumors in an NK cell-dependent manner, as NK cell depletion restored tumor growth. This effect persisted and remained dependent on NK cells in Rag2 knockout mice (lacking T and B cells), but not in NSG mice (lacking T-, B- and NK-cells). Furthermore, EHMT2 and TGF-β1 inhibitors suppressed tumors in immunocompetent, but not in immunodeficient mice. These findings establish EHMT2 as a suppressor of NK cell-mediated anti-tumor immunity and a promising therapeutic target.
Insights
EHMT2 inhibition boosts Natural Killer (NK) cell anti-tumor activity by enhancing cancer cell elimination. This discovery reveals EHMT2 as a key target for improving cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Epigenetics
Background:
- Natural Killer (NK) cells are crucial for tumor surveillance, but the mechanisms controlling their anti-tumor functions are not fully understood.
- Identifying regulators of NK cell-mediated cytotoxicity is essential for developing novel cancer immunotherapies.
Purpose of the Study:
- To investigate the role of histone methyltransferase EHMT2 in NK cell-mediated anti-tumor immunity.
- To evaluate EHMT2 inhibition as a therapeutic strategy to enhance NK cell cytotoxicity against various cancers.
Main Methods:
- Investigated EHMT2's role in NK cell cytotoxicity using in vitro and in vivo cancer models.
- Analyzed molecular changes, including AZGP1, TGF-β1, MICB, and ULBP3 levels, following EHMT2 inhibition.
- Utilized immunocompetent, Rag2 knockout, and NSG mouse models to assess NK cell-dependent anti-tumor effects.
Main Results:
- EHMT2 inhibition in cancer cells significantly enhanced NK cell-mediated elimination of uveal melanoma, breast, and pancreatic cancers.
- EHMT2 loss led to increased AZGP1 and decreased TGF-β1, resulting in elevated NKG2D ligands (MICB, ULBP3) and enhanced NK cell function.
- EHMT2 inhibition suppressed tumors in a manner dependent on NK cells, confirmed in immunocompetent and Rag2 knockout mice.
Conclusions:
- EHMT2 acts as a suppressor of NK cell-mediated anti-tumor immunity.
- Targeting EHMT2 represents a promising therapeutic strategy to augment NK cell-based cancer immunotherapy.
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