# Multi-omics integration identifies PGAP3 as a tumor-intrinsic factor associated with CD8+ T-cell exclusion in prostate cancer

## TL;DR

This study finds that PGAP3 is a gene linked to immune evasion in prostate cancer, contributing to a 'cold' tumor environment with few T-cells.

## Contribution

The novel contribution is identifying PGAP3 as a tumor-intrinsic factor associated with CD8+ T-cell exclusion in prostate cancer.

## Key findings

- PGAP3 is selectively overexpressed in malignant epithelial subpopulations and is a risk gene in prostate cancer.
- PGAP3-high cells show increased metabolic activity and reduced CD8+ T-cell infiltration.
- Silencing PGAP3 impairs cancer cell proliferation, clonogenic growth, and migration in vitro.

## Abstract

Prostate cancer (PCa) is prototypically immunologically “cold”, characterized by low tumor mutational burden, sparse CD8+ T-cell infiltration, and resistance to immune checkpoint blockade. The tumor cell–intrinsic programs driving immune evasion in this context remain incompletely defined.

We integrated transcriptome-wide Mendelian randomization of PCa GWAS and eQTL data with multi-cohort bulk and single-cell RNA sequencing, spatial transcriptomics, and immune profiling to prioritize candidate genes. Focusing on PGAP3, we characterized its metabolic and immune correlates, and validated the effects of PGAP3 knockdown on proliferation, clonogenicity, and migration in C4-2 and DU145 cells.

PGAP3 was consistently prioritized as a risk gene and was selectively overexpressed in malignant epithelial subpopulations. PGAP3-high cells exhibited increased metabolic activity (biotin, aspartate/asparagine, and sulfur metabolism), coinciding with reduced CXCL14, TNFSF13B, and TNFSF18 expression, lower CD8+ T-cell infiltration, and higher immune-exclusion scores. Functionally, PGAP3 silencing significantly impaired proliferation, clonogenic growth, and migration in vitro.

Our findings identify PGAP3 as a tumor-intrinsic gene associated with metabolic reprogramming and a CTL/CD8+-low immune contexture in PCa, supporting PGAP3 as a potential marker of the immune-cold tumor microenvironment and motivate future mechanistic studies in immunocompetent systems.