Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.

Area of Science:

• Gastroenterology
• Oncology
• Immunology

Background:

• Hereditary diffuse gastric cancer (HDGC) is linked to germline CDH1 variants and early-stage gastric adenocarcinoma with intramucosal signet ring cells (SRCs).
• The molecular mechanisms driving malignant transformation and dormancy of SRCs in HDGC remain largely unknown.
• Understanding these early events is crucial for developing effective cancer interception strategies.

Purpose of the Study:

• To investigate the molecular and immune microenvironment of early-stage SRCs in patients with HDGC.
• To identify potential molecular drivers or suppressors of SRC initiation and dormancy.
• To explore the role of the tumor immune microenvironment in the pathogenesis of HDGC.

Main Methods:

• Whole-exome bulk RNA sequencing (RNA-seq) was performed on laser-capture microdissected (LCM) SRCs and adjacent non-SRC epithelium (NEP).
• Analysis included differential gene expression (DEG), pathway enrichment analysis, and CIBERSORTx for immune cell deconvolution.
• Immunohistochemistry (IHC) was used to confirm findings for specific immune cell markers (FOXP3, CD4, HLA-DR).

Main Results:

• No significant upregulation of oncogenic pathways was observed in SRCs; instead, pathways related to T-cell signaling were enriched.
• CIBERSORTx predicted and IHC confirmed an increase in regulatory T cells (Tregs) and CD4+ T cells within SRC regions.
• Elevated CD4+ T cells correlated with observed SRC dormancy, while Treg upregulation suggested a potential immune escape mechanism.

Conclusions:

• The tumor immune microenvironment is intimately associated with stage IA gastric SRCs in HDGC.
• Immune cell populations, particularly Tregs, may play a significant role in regulating SRC behavior and dormancy.
• These findings highlight the potential of immune-directed therapies for cancer interception in diffuse-type gastric cancer.