KMT2D Induces M1 Macrophage Polarization to Repress Non-small Cell Lung Cancer Progression via Transcription Activation of ITGAL

TL;DR

This study shows that KMT2D helps M1 macrophages fight non-small cell lung cancer by boosting ITGAL expression, offering a new potential treatment target.

Contribution

The study reveals a novel mechanism where KMT2D activates ITGAL to induce M1 macrophage polarization and suppress NSCLC.

Findings

KMT2D and ITGAL are underexpressed in NSCLC tissues and cells.

KMT2D overexpression promotes M1 macrophage polarization and reduces NSCLC cell growth and metastasis.

ITGAL inhibition reverses the anti-cancer effects of KMT2D overexpression.

Abstract

Recent evidence has demonstrated the crucial role of macrophage polarization in promoting non-small cell lung cancer (NSCLC) progression within the tumor microenvironment.

This study investigated the possible regulatory mechanism of macrophage polarization during NSCLC development.

The proportion of M1/M2 macrophages was examined by flow cytometry. The expression of macrophage markers and target molecules was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemical staining. Non-small cell lung cancer cells were treated with conditioned medium (CM) from THP-1 macrophages. Cell counting kit-8 (CCK-8), scratch, and transwell assays were used to assess NSCLC cell growth and metastasis. Gene promoter activity was evaluated by dual-luciferase reporter assay. A xenograft model was adopted to determine NSCLC growth in vivo.

Histone-lysine N-methyltransferase 2D (KMT2D) and integrin subunit alpha L (ITGAL) were lowly expressed in NSCLC tissues and cells. The KMT2D overexpression facilitated the polarization of macrophages from M2 to M1 type, which repressed the growth, migration, and invasion of NSCLC cells. Mechanistically, KMT2D promoted the transcription and expression of ITGAL. Inhibition of ITGAL abrogated KMT2D overexpression-mediated M1 macrophage polarization and its anti-cancer effects on NSCLC.

The KMT2D transcriptionally activated ITGAL to trigger M1 macrophage polarization, thereby delaying NSCLC progression. Our findings suggest KMT2D as a potential therapeutic target for NSCLC.

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