Signature Construction Associated with Tumor-Infiltrating Macrophages Identifies IRF8 as a Novel Biomarker for Immunotherapy in Advanced Gastric Cancer

TL;DR

This study identifies IRF8 as a new biomarker for predicting immunotherapy response in advanced gastric cancer, based on its role in shaping the tumor immune environment.

Contribution

The study introduces a novel gene signature linked to M1-like TAMs and identifies IRF8 as a key biomarker for immunotherapy in gastric cancer.

Findings

The gene signature is an independent prognostic indicator for advanced gastric cancer.

IRF8 overexpression promotes an anti-tumor immune environment and enhances response to anti-PD-1 therapy.

Syngeneic mouse models showed reduced tumor growth with IRF8 overexpression and anti-PD-1 treatment.

Abstract

Advanced gastric cancer (AGC) is characterized by poor prognosis and limited responsiveness to immunotherapy. Tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapeutic outcomes. In this study, we developed a novel gene signature associated with M1-like TAMs using data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) to predict prognosis and immunotherapy response. This gene signature was determined as an independent prognostic indicator for AGC, with high-risk patients exhibiting an immunosuppressive tumor immune microenvironment (TIME) and poorer survival outcomes. Furthermore, Interferon regulatory factor 8 (IRF8) was identified as a key gene and validated through in vitro and in vivo experiments. IRF8 overexpression reshaped the suppressive TIME, leading to an increased presence of M1-like TAMs, IFN-γ+ CD8+ T cells, and Granzyme B+ CD8+ T cells. Notably, the combination of IRF8 overexpression and anti-PD-1 therapy significantly inhibited tumor growth in syngeneic mouse models. AGC patients with elevated IRF8 expression were found to be more responsive to anti-PD-1 treatment. These findings highlight potential biomarkers for prognostic evaluation and immunotherapy in AGC, offering insights that could guide personalized treatment strategies.

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