# DOT1L promotes immune evasion in lung adenocarcinoma through H3K79me2-mediated epigenetic activation of immune checkpoints

## TL;DR

DOT1L helps lung cancer cells avoid immune detection by activating immune checkpoints through epigenetic changes, suggesting it could be a new target for cancer therapy.

## Contribution

This study reveals a novel epigenetic mechanism by which DOT1L promotes immune evasion in lung adenocarcinoma.

## Key findings

- DOT1L expression correlates with poor prognosis and reduced immune cell infiltration in lung adenocarcinoma.
- Pharmacological inhibition of DOT1L reduces immune checkpoints and improves survival in preclinical models.
- DOT1L-mediated H3K79me2 activates JAK1/STAT3 and immune checkpoint genes like PD-L1, LAG3, and CD276.

## Abstract

The histone methyltransferase DOT1L, the sole enzyme catalyzing H3K79 methylation, is increasingly implicated in cancer progression, yet its role in shaping the tumor immune microenvironment (TME) remains unclear. Here, we demonstrate that DOT1L orchestrates immune evasion in lung adenocarcinoma (LUAD) through epigenetic activation of multiple immune checkpoints. Integrative analysis of TCGA and single-cell RNA-seq data revealed that high DOT1L expression correlates with poor prognosis, diminished cytotoxic immune-cell infiltration, and upregulation of inhibitory checkpoints (PD-L1, PD-1, LAG3, CD276, etc.). Mechanistically, ChIP-seq identified DOT1L-mediated H3K79me2 enrichment at promoters of JAK1/STAT3 genes, and some immune checkpoints, including LAG3, CD276, etc. Pharmacological DOT1L inhibition (SGC0946) suppressed the JAK1/STAT3/PD-L1 axis, reduced PD-1+ T cells in a vitro immune microenvironment. In vivo, SGC0946 attenuated lung metastasis, improved survival, and remodeled the TME by downregulating PD-L1, LAG3, and CD276 expression, reduced PD-1+ T cells subsets, and alongside with enhanced TNF-α, IFN-γ production. Clinical LUAD specimens further validated the correlation between DOT1L expression, STAT3 activation, and checkpoint upregulation, particularly in metastatic disease. Our findings identify DOT1L as an epigenetic linchpin of immune suppression.