Abstract
BackgroundThe role of tumor–stroma interactions in tumor immune microenvironment (TME) is attracting attention. We have previously reported that cancer-associated fibroblasts (CAFs) contribute to the progression of peritoneal metastasis (PM) in gastric cancer (GC), and M2 macrophages and mast cells also contribute to TME of PM. To elucidate the role of CAFs in TME, we established an immunocompetent mouse PM model with fibrosis, which reflects clinical features of TME. However, the involvement of CAFs in the immunosuppressive microenvironment remains unclear. In this study, we investigated the efficacy of Tranilast at modifying this immune tolerance by suppressing CAFs.MethodsThe interaction between mouse myofibroblast cell line LmcMF and mouse GC cell line YTN16 on M2 macrophage migration was investigated, and the inhibitory effect of Tranilast was examined in vitro. Using C57BL/6J mouse PM model established using YTN16 with co-inoculation of LmcMF, TME of resected PM treated with or without Tranilast was analyzed by immunohistochemistry.ResultsThe addition of YTN16 cell-conditioned medium to LmcMF cells enhanced CXCL12 expression and stimulated M2 macrophage migration, whereas Tranilast inhibited the migration ability of M2 macrophages by suppressing CXCL12 secretion from LmcMF. In PM model, Tranilast inhibited tumor growth and fibrosis, M2 macrophage, and mast cell infiltration and significantly promoted CD8 + lymphocyte infiltration into the tumor, leading to apoptosis of cancer cells by an immune response.ConclusionTranilast improved the immunosuppressive microenvironment by inhibiting CAF function in a mouse PM model. Tranilast is thus a promising candidate for the treatment of PM.
Highlights
Gastric cancer is one of the most common malignancies in East Asia, and peritoneal metastasis (PM) has a poor prognosis with a 1-year survival rate of approximately 40% [1, 2]
The addition of YTN16 cells-conditioned medium (CM) to LmcMF cells significantly induced the migration ability of M2 macrophages compared to monoculture of YTN16 cells (106.5 ± 9.1 cells vs. 48.2 ± 3.9 cells, p < 0.01). 24 h after the addition of YTN16 cell-CM to LmcMF cells, the number of M2 macrophages penetrating to the lower surface of the transwell chamber was significantly decreased in the Tranilasttreated group compared to the control group (31.0 ± 1.4 cells vs. 106.5 ± 9.1 cells, p < 0.01) (Fig. 1)
The interaction of LmcMF cells with YTN16 cells increases C–X–C motif chemokine ligand 12 (CXCL12) production levels. These results indicate that the effect of LmcMF on M2 macrophage migration potency may be mediated by paracrine effects
Summary
Gastric cancer is one of the most common malignancies in East Asia, and peritoneal metastasis (PM) has a poor prognosis with a 1-year survival rate of approximately 40% [1, 2]. Of CD8+ cells and high infiltration of M2 macrophages by various cytokines or chemokines from cancer-associated fibroblasts (CAFs) [10] These immunosuppressive states lead to resistance to immune checkpoint inhibitors (ICIs) and to chemotherapy. PM characterized by abundant fibrous stroma is considered to be caused by crosstalk between cancer cells and CAFs with Transforming growth factor β (TGF-β), or between mast cells and CAFs by interleukin-17A (IL-17A) [11] This fibrosis induces occlusion of the luminal organs, such as intestinal obstruction, hydronephrosis, and obstructive jaundice, and interferes with the delivery of chemotherapeutic agents due to its high intra-tumor pressure [4]. Tranilast is a promising candidate for the treatment of PM
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