Distinct Immunosuppressive Tumor Microenvironment in Gastric Cancer With Peritoneal Metastasis

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• Immunotherapy combined with chemotherapy is standard palliative treatment for gastric cancer.
• Peritoneal metastases in gastric cancer often exhibit resistance to immunotherapy.
• Understanding the tumor immune microenvironment (TIME) is crucial for improving treatment efficacy.

Purpose of the Study:

• To comprehensively analyze the TIME in peritoneal metastases of gastric cancer.
• To identify key characteristics of the TIME that contribute to immunotherapy resistance.

Main Methods:

• Collected single-cell suspensions from malignant ascites and peripheral blood mononuclear cells (PBMCs) from 27 gastric cancer patients.
• Analyzed cell-free fluids from ascites and plasma using multiplex enzyme-linked immunosorbent assay (ELISA).
• Evaluated paired primary gastric tumors and metastatic peritoneal tumors using multiplex immunohistochemistry (IHC).

Main Results:

• T cells in malignant ascites displayed increased immune checkpoint receptors and terminal exhaustion.
• Elevated levels of soluble immunosuppressive factors (e.g., MMPs, TGF-β1, VEGF) were found in malignant ascites.
• Metastatic peritoneal tumors showed reduced CD4+ and CD8+ T cell densities and exhibited immunosuppressive TIME subtypes.

Conclusions:

• Gastric cancer with peritoneal metastasis presents distinct immunosuppressive tumor immune microenvironments.
• These findings highlight potential targets for overcoming immunotherapy resistance in peritoneal disease.