Epigenetic Suppression of Histone Deacetylase 4 Boosts T Cell Homing via CXCR3 in Lung Cancer: A Step Toward Ultrasound-Guided Immunotherapy

Abstract

Background:

Lung cancer is the biggest reason of cancer-correlated death worldwide, owing primarily to immune evasion and poor response to current immunotherapies.

Objective:

The aim of this work was focused on the immunomodulatory effect of histone deacetylase 4 (HDAC4) in tumor immunological milieu, specifically CD8⁺ T cell trafficking.

Methods:

Quantitative RT-PCR, immunofluorescence labeling, and FISH tests were used to determine HDAC4 and CXCR3 expression and location in lung cancer tissues. Flow cytometry assessed CD8⁺ T cell function, and histological analysis revealed tumor development.

Results:

Our results showed that HDAC4 was highly overexpressed in lung tumor samples, and it was associated with advanced clinical stage, lymph node metastases, and a worse overall survival rate. HDAC4 decreased CXCR3 expression, affecting CD8⁺ T cell infiltration and effector function. HDAC4 knockdown increased CD8⁺ T cell cytotoxicity, whereas CXCR3 inhibition reversed this effect. HDAC4 expression predicted poor survival with a ROC AUC of 0.78. SB939 treatment raised CXCR3 expression by 2.4 times and CD8⁺ infiltration by 39%.

Conclusion:

These findings point to HDAC4 as a crucial epigenetic regulator of immune cell trafficking in lung cancer. Given the growing interest in ultrasound-assisted medication delivery and immunological priming, our findings point to HDAC4 as a viable therapeutic target in ultrasound-guided immunomodulatory methods for lung cancer.