Inhibition of SUMOylation Induces Adaptive Antitumor Immunity against Pancreatic Cancer through Multiple Effects on the Tumor Microenvironment.

Autor:	Erdem S; Moores Cancer Center, UC San Diego, La Jolla, California., Lee HJ; Moores Cancer Center, UC San Diego, La Jolla, California., Shankara Narayanan JSN; Moores Cancer Center, UC San Diego, La Jolla, California., Tharuka MDN; Moores Cancer Center, UC San Diego, La Jolla, California., De la Torre J; Division of Surgical Oncology, Department of Surgery, UC San Diego, La Jolla, California., Ren T; Division of Surgical Sciences, Department of Surgery, UC San Diego, La Jolla, California.; Graduate Program in Chemistry and Biochemistry, UC San Diego, La Jolla, California., Kuang Y; Division of Surgical Sciences, Department of Surgery, UC San Diego, La Jolla, California.; Graduate Program in Chemistry and Biochemistry, UC San Diego, La Jolla, California., Abeywardana T; Moores Cancer Center, UC San Diego, La Jolla, California., Li K; Division of Surgical Oncology, Department of Surgery, UC San Diego, La Jolla, California., Berger AJ; Takeda Development Center Americas Inc., Lexington, Massachusetts., Lowy AM; Moores Cancer Center, UC San Diego, La Jolla, California.; Division of Surgical Oncology, Department of Surgery, UC San Diego, La Jolla, California., White RR; Moores Cancer Center, UC San Diego, La Jolla, California.; Division of Surgical Oncology, Department of Surgery, UC San Diego, La Jolla, California., Chen Y; Moores Cancer Center, UC San Diego, La Jolla, California.; Division of Surgical Sciences, Department of Surgery, UC San Diego, La Jolla, California.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Aug 16, pp. OF1-OF16. Date of Electronic Publication: 2024 Aug 16.
DOI:	10.1158/1535-7163.MCT-23-0572
Abstrakt:	Improvement of outcome in patients with pancreatic ductal adenocarcinoma (PDAC) requires exploration of novel therapeutic targets. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology, yet SUMOylation occurs in a variety of cell types. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical-stage compound, TAK-981. In contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit conferred by TAK-981 in vivo is dependent on the presence of T cells, suggesting that induction of adaptive antitumor immunity is an important antitumor effect of SUMOylation inhibition in vivo. To understand how this adaptive antitumor immunity is promoted, we investigated how SUMOylation inhibition in vivo alters major cell types/subtypes and their communications in the PDAC tumor microenvironment by performing transcriptomic analyses at single-cell resolution, which allowed mapping of cells in our orthotopic mouse model to cells in human PDAC tumors based on gene expression profiles. Findings are further validated by flow cytometry, immunofluorescence, IHC, western blots, and qPCR. The single-cell transcriptome dataset provided here suggests several combination strategies to augment adaptive immune responses that are necessary for durable disease control in patients with PDAC. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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