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Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer


ABSTRACT: Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33 on PM-associated TIME. Immunocompetent mice were used to investigate the role of IL-33 in development of abdominal dissemination and host outcome. Murine (m) and human (h) gastric cancer cells were tested for their response to IL-33 using qRT-PCR, flow cytometry, and immunofluorescence. The survival was significantly prolonged in patients with high IL-33 mRNA expression. Intraperitoneal administration of IL-33 could induce the celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 (GATA3) signaling pathway. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) showed a synergistic antitumor effect. Intraperitoneal administration of IL-33 inducing local inflammatory milieu provided a novel approach for treating metastatic peritoneal malignancies, which was combined with TAM reprogramming to reshape TIME to achieve better treatment efficacy.

SUBMITTER: Dr. Keying Che 

PROVIDER: S-SCDT-10_15252-EMMM_202217321 | biostudies-other |

REPOSITORIES: biostudies-other

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