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  • Title: Intraperitoneal neutrophils activated by KRAS-induced ovarian cancer exert antitumor effects by modulating adaptive immunity.
    Author: Yoshida M, Taguchi A, Kawana K, Ogishima J, Adachi K, Kawata A, Nakamura H, Sato M, Fujimoto A, Inoue T, Tomio K, Mori M, Nagamatsu T, Arimoto T, Koga K, Hiraike OW, Oda K, Kiyono T, Osuga Y, Fujii T.
    Journal: Int J Oncol; 2018 Oct; 53(4):1580-1590. PubMed ID: 30066851.
    Abstract:
    Increased neutrophil counts are a hallmark of a poor prognosis for cancer. We previously reported that KRAS promoted tumorigenesis and increased neutrophil counts in a mouse peritoneal cancer model. In the current study, we evaluated the role of increased neutrophils in cancer progression, as well as their influence on the intraperitoneal microenvironment. A mouse peritoneal cancer model was established using the KRAS-transduced mouse ovarian cancer cell line, ID8-KRAS. Neutrophil function was assessed by neutrophil depletion in ID8-KRAS mice. Neutrophil depletion markedly accelerated tumor formation; this was accompanied by an increase in interleukin-6 concentrations in ascites. Neutrophil depletion significantly decreased the amount of local and systemic CD8+ T cells, while increasing the amount of local CD4+ T cells, accompanied by an increased amount of monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) (P<0.05). The roles of peritoneal neutrophils (PENs) in CD8+ T cell activation were assessed in vitro. PENs of ID8-KRAS mice had a strong potential to enhance T cell proliferation with a higher expression of the T cell costimulatory molecules OX40 ligand (OX40L) and 4-1BB ligand (4-1BBL), as compared with peripheral blood neutrophils (PBNs). These findings suggest that neutrophils recruited into the KRAS-induced tumor microenvironment (TME) have antitumor properties with the potential to modulate the numbers of M-MDSCs and Tregs and activate CD8+ T cells through T cell costimulatory molecules.
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