# Loss of EHMT2 enhances NK cell-driven anti-tumor immunity through TGF-β1 suppression

## TL;DR

EHMT2 inhibition boosts NK cell activity against tumors by reducing TGF-β1 and increasing MICB, offering a new cancer treatment strategy.

## Contribution

EHMT2 is identified as a novel epigenetic suppressor of NK cell-mediated anti-tumor immunity, with EHMT2 inhibition shown to enhance cytotoxicity through TGF-β1 suppression.

## Key findings

- EHMT2 inhibition enhances NK cell-mediated cytotoxicity in uveal melanoma, breast, and pancreatic cancers.
- Loss of EHMT2 increases MICB and chemokine expression, and decreases TGF-β1, promoting NK cell activity.
- Tumor suppression via EHMT2 inhibition is dependent on NK cells in immunocompetent mice.

## 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.

EHMT2 has been identified as a key epigenetic barrier to NK cell-driven tumor immunity. Its inhibition stimulates NK cell-mediated cytotoxicity by suppressing TGF-β1 and upregulating MICB, and chemokines in cancer cells.

EHMT2 inhibition was shown to enhance NK cell-mediated killing across uveal melanoma, breast, and pancreatic cancer models.AZGP1 was upregulated upon EHMT2 inhibition and identified as a direct transcriptional target of EHMT2 required for suppressing TGF-β1 expression.In cancer cells, loss of EHMT2 led to increased expression of MICB, which was required for NK cell-mediated cytotoxicity.TGF-β1 inhibition was sufficient to restore NK cell-mediated cytotoxicity and chemokine-driven tumor infiltration, mimicking the effects of EHMT2 loss.Tumor suppression upon EHMT2 inhibition was shown to be NK cell-dependent in immunocompetent mice.

EHMT2 inhibition was shown to enhance NK cell-mediated killing across uveal melanoma, breast, and pancreatic cancer models.

AZGP1 was upregulated upon EHMT2 inhibition and identified as a direct transcriptional target of EHMT2 required for suppressing TGF-β1 expression.

In cancer cells, loss of EHMT2 led to increased expression of MICB, which was required for NK cell-mediated cytotoxicity.

TGF-β1 inhibition was sufficient to restore NK cell-mediated cytotoxicity and chemokine-driven tumor infiltration, mimicking the effects of EHMT2 loss.

Tumor suppression upon EHMT2 inhibition was shown to be NK cell-dependent in immunocompetent mice.

EHMT2 has been identified as a key epigenetic barrier to NK cell-driven tumor immunity. Its inhibition stimulates NK cell-mediated cytotoxicity by suppressing TGF-β1 and upregulating MICB, and chemokines in cancer cells.