Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer.

Autor:	Ye J; Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan.; Department of Pharmacology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan., Suizu F; Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan., Yamakawa K; Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan., Mukai Y; Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan., Yoneyama H; TME Therapeutics Inc., Minato-ku, Tokyo 105-0021, Japan., Kondo J; Department of Materials and Life Sciences, Sophia University, Chiyoda-ku, Tokyo 102-8554, Japan., Kato M; Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan., Nishiyama A; Department of Pharmacology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan., Yahagi N; Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan., Kadota K; Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Oncology [Mol Ther Oncol] 2024 May 03; Vol. 32 (2), pp. 200812. Date of Electronic Publication: 2024 May 03 (Print Publication: 2024).
DOI:	10.1016/j.omton.2024.200812
Abstrakt:	The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G + MDSCs in vivo . Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro , CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33 + MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15 + MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs. Competing Interests: H.Y. is the founder of TME Therapeutics Inc. M.K. received payments for lectures from Boston Scientific Japan, Olympus Japan, AstraZeneca, Takeda Pharmaceutical, EA Pharma, and Daiichi Sankyo, and supports for attending meetings from Olympus Japan. N.Y. received free provision of test agents from TME therapeutics, and a research grant for the present study from the Japan Agency for Medical Research and Development (AMED), research grants from Sanwa Kagaku Kenkyujo and Kaigen Pharma, and consulting fees from Olympus Japan, Top corporation, Fujifilm and Boston Scientific Japan, and payments for lectures from Olympus Japan, AstraZeneca, Daiichi Sankyo. Takeda Pharmaceuticals, Ohtsuka Pharmaceutical and EA Pharma. (© 2024 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu