# The Identification of LA-tumor associated macrophages in immune modulation via amyloid-beta precursor protein/CD74 signal pathway in gastric cancer: a predictive module and machine learning

## TL;DR

This study identifies a specific type of tumor-associated macrophage in gastric cancer that contributes to immune evasion and proposes a predictive model for prognosis and treatment.

## Contribution

The study introduces a novel predictive module based on LA-TAM and identifies the APP/CD74 pathway as a potential immunotherapy target in gastric cancer.

## Key findings

- LA-TAM shows high plasticity and metabolic reprogramming in the gastric cancer microenvironment.
- APP/CD74 signaling increases PD-1 expression in macrophages, promoting immune evasion.
- The LA-TAM-based model demonstrates strong prognostic performance across multiple cohorts.

## Abstract

Tumor-associated macrophages (TAMs) play a critical role in cancer immune microenvironment, modulating immune evasion. The prognostic role of TAMs gives insights into the immune landscape and therapeutic targets in gastric cancer (GC).

GC microenvironment was analyzed via single-cell and bulk RNA-seq data from public databases. TAM subtypes were then identified via dimensionality reduction and annotation under quality control. TAM differentiation and function were evaluated by pseudo-time analysis, cell communication, molecular docking, and key gene enrichment. A predictive model based on LA-TAM was established. Amyloid-β precursor protein (APP) expression level and its effect on macrophage programmed death-1 (PD-1) expression was validated in vitro.

In GC microenvironment, epithelial cells and fibroblasts were downregulated, while B cells, CD8+ T cells and myeloid cells were enriched. Among TAM subtypes, LA-TAM exhibited the potential of differentiation, metabolic reprogramming, and high plasticity. When LA-TAM interacts with endothelial cells, APP/Collagen pathway was activated, in which PD-1 expression was up-regulated by APP/CD74 activation. The LA-TAM-based predictive model showed significant performance among multiple cohorts (C-index >0.5, HR = 1.63, p<0.001). APP positively correlated with PD-1 expression. In GC THP-1 monocytes, APP was enriched and stimulated PD-1 expression.

LA-TAM plays a key role in immune suppression and metabolic regulation in GC. Its key genes form a high-precision prognosis model, and endothelial cell-expressed APP may promote immune evasion by enhancing macrophage PD-1 expression, suggesting a potential target for immunotherapy.