Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice

Ye, Juanjuan; Suizu, Futoshi; Yamakawa, Keiko; Mukai, Yukinori; Kato, Motohiko; Yoneyama, Hiroyuki; Yahagi, Naohisa; Matsuda, Yoko

doi:10.1002/eji.202250160

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…On the one hand, MDSC aggregates secrete a large number of immunosuppressive cytokines, including arginase-1 (Arg 1), interleukin-6 (IL-6), and interleukin-10 (IL-10), causing a highly immunosuppressed state and promoting tumour evasion and metastasis by immune cells in PC [7,8]. On the other hand, MDSCs can also secrete indoleamine 2,3-dioxygenase 1 (IDO), causing CD8 + T-cell depletion and antagonizing the effects of immune checkpoint drugs, which lead to the progression of PC [9,10]. Therefore, the clearance of MDSCs can signi cantly enhance the effect of immunotherapy in PC and reverse PD-1 drug resistance [11].…”

Section: Introductionmentioning

confidence: 99%

Exogenous HMGB1 promotes pancreatic cancer progression by supporting the crosstalk between tumor and myeloid-derived suppressor cell

Wang,

Wei,

San

et al. 2024

Preprint

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Background The main reasons pancreatic cancer (PC) is difficult to treat are high tissue fibrosis and a strong immunosuppressive microenvironment. Therefore, it is necessary to elucidate the cause and mechanism of tumour immunosuppressive microenvironment formation. High-mobility group Box 1 (HMGB1) is a highly conserved nuclear protein that is widely distributed in mammalian cells and plays an important role in tumours. However, the functions and mechanisms of HMGB1 in the PC tumour microenvironment remain controversial. Here, we report a novel role for HMGB1 in the formation of the PC immune microenvironment. Methods In this study, the HMGB1 expression level of samples was detected in PC patients and TCGA database. The relative expression of HMGB1 in serum and tissues was evaluated by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T cells in tumours from PC xenograft mouse models treated with HMGB1. Vascular density and cytokine expression levels in tumour tissues were measured by immunohistochemistry (IHC). HMGB1-associated differentially expressed genes from the GEPIA database were used to analyse GO terms and KEGG pathways. Subsequently, the expression of related proteins was detected by Western blotting. Results The expression level of HMGB1 was higher in PC tumours than in normal tissues. High levels of HMGB1 predict poor overall survival in PC patients, suggesting its potential clinical significance in PC prognosis. The mouse model results show that HMGB1 significantly promotes tumour growth. We further found that CD69+CD8+ T cells were markedly decreased in HMGB1-treated mice. Furthermore, after treatment with HMGB1, the infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) into tumour tissues was increased. The IHC results showed that HMGB1 promoted the expression of intracellular inflammatory factors and neovascularization. Mechanistically, the results indicated that HMGB1 significantly enhanced the expression of CXCL2 chemokines that attract MDSCs to tumours. HMGB1 upregulates CXCL2 expression through the MAPK pathway. Conclusion In conclusion, HMGB1 plays an unexpected role in cancer metastasis by promoting microvessel formation and cytokine CXCL2 expression mediated by the MAPK pathway to recruit MDSC aggregation, which in turn creates an immunosuppressive microenvironment. Thus, HMGB1 may be an important mediator and a potential therapeutic target for regulating PC progression.

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Section: Introductionmentioning

confidence: 99%

Exogenous HMGB1 promotes pancreatic cancer progression by supporting the crosstalk between tumor and myeloid-derived suppressor cell

Wang,

Wei,

San

et al. 2024

Preprint

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

Ye,

Suizu,

Yamakawa

et al. 2024

Molecular Therapy: Oncology

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Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes

Mueller,

Thomas,

Dalgaard

et al. 2024

Essays in Biochemistry

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Diabetes Type 1 and Type 2 are widely occurring diseases. In spite of a vast amount of biomedical literature about diabetic processes in general, links to certain biological processes are only becoming evident these days. One such area of biology is the sulfation of small molecules, such as steroid hormones or metabolites from the gastrointestinal tract, as well as larger biomolecules, such as proteins and proteoglycans. Thus, modulating the physicochemical propensities of the different sulfate acceptors, resulting in enhanced solubility, expedited circulatory transit, or enhanced macromolecular interaction. This review lists evidence for the involvement of sulfation pathways in the maintenance of functional pancreatic beta-cell mass and the implications for diabetes, grouped into various classes of sulfated biomolecule. Complex heparan sulfates might play a role in the development and maintenance of beta-cells. The sulfolipids sulfatide and sulfo-cholesterol might contribute to beta-cell health. In beta-cells, there are only very few proteins with confirmed sulfation on some tyrosine residues, with the IRS4 molecule being one of them. Sulfated steroid hormones, such as estradiol-sulfate and vitamin-D-sulfate, may facilitate downstream steroid signaling in beta-cells, following de-sulfation. Indoxyl sulfate is a metabolite from the intestine, that causes kidney damage, contributing to diabetic kidney disease. Finally, from a technological perspective, there is heparan sulfate, heparin, and chondroitin sulfate, that all might be involved in next-generation beta-cell transplantation. Sulfation pathways may play a role in pancreatic beta-cells through multiple mechanisms. A more coherent understanding of sulfation pathways in diabetes will facilitate discussion and guide future research.

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Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice

Cited by 3 publications

References 41 publications

Exogenous HMGB1 promotes pancreatic cancer progression by supporting the crosstalk between tumor and myeloid-derived suppressor cell

Exogenous HMGB1 promotes pancreatic cancer progression by supporting the crosstalk between tumor and myeloid-derived suppressor cell

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

Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes

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