Characterization of tumor immune microenvironment in gastric cancer patients with peritoneal metastasis.

Abstract

e16054 Background: Immunotherapy combined with chemotherapy is the standard palliative systemic treatment for locally advanced unresectable or metastatic gastric cancer (GC). However, patients with GC and peritoneal metastases are resistant to immunotherapy. To enhance the clinical benefits for these patients, a comprehensive evaluation of the tumor immune microenvironments (TIMEs) in peritoneal metastasis and malignant ascites is essential. This study aimed to comprehensively analyze the TIME in patients with GC and peritoneal metastases. Methods: We obtained paired single-cell suspensions from malignant ascites and peripheral blood mononuclear cells (PBMCs) from peripheral blood of 27 patients with GC and peritoneal metastasis for multicolor fluorescence-activated cell sorting analysis. Also, paired cell-free fluids of malignant ascites and plasma were obtained from 15 patients with GC and peritoneal metastasis, and cell-free fluids from non-cancerous ascites were collected from 15 patients with Child-Pugh B/C liver cirrhosis for multiplex enzyme-linked immunosorbent assay analysis. Additionally, paired primary gastric tumor and synchronous metastatic peritoneal tumor samples were collected from 12 patients for multiplex immunohistochemistry analysis. Results: The proportions of T cells expressing immune checkpoint receptors, including programmed cell death-1 (PD-1), T-cell immunoglobulin and mucin-domain containing 3 (TIM-3), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), lymphocyte activation gene 3 (LAG-3), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), were significantly increased in malignant ascites compared to paired PBMCs. The CD8 + T cells in malignant ascites exhibited a higher proportion of the Eomes high T-bet low phenotype compared to PMBCs, indicating a more terminally exhausted state. Additionally, the T cells in malignant ascites showed a higher proportion of CD39 + or CD103 + cells, reflecting greater tumor antigen reactivity. Levels of soluble immunosuppressive factors, including matrix metalloproteinase (MMP)-2, MMP-7, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and angiopoietin-2 (ANGPT-2), were significantly higher in cell-free fluids of malignant ascites than in the paired plasma and benign ascites. The densities of CD4 + and CD8 + T cells were significantly lower in metastatic peritoneal tumors than in primary gastric tumors. Metastatic peritoneal tumors exhibited more immunosuppressive immune-desert (83.3%) and intrinsic induction type (66.7%) TIMEs than primary gastric tumors. Conclusions: Our findings revealed unique peritoneal immunosuppressive TIMEs in patients with GC and peritoneal metastasis, suggesting the potential of co-blockade of immune checkpoints and soluble immunosuppressive factors as a treatment option.