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Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma

BACKGROUND: Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). METHODS: On...

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Autores principales: Jiang, Yongsheng, Han, Lijie, Yang, Jian, Yang, Minwei, Zhang, Jian, Xue, Meilin, Zhu, Youwei, Xiong, Cheng, Shi, Minmin, Zhao, Shiwei, Shen, Baiyong, Xu, Zhiwei, Jiang, Lingxi, Chen, Hao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361881/
https://www.ncbi.nlm.nih.gov/pubmed/37097516
http://dx.doi.org/10.1007/s00262-023-03438-y
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author Jiang, Yongsheng
Han, Lijie
Yang, Jian
Yang, Minwei
Zhang, Jian
Xue, Meilin
Zhu, Youwei
Xiong, Cheng
Shi, Minmin
Zhao, Shiwei
Shen, Baiyong
Xu, Zhiwei
Jiang, Lingxi
Chen, Hao
author_facet Jiang, Yongsheng
Han, Lijie
Yang, Jian
Yang, Minwei
Zhang, Jian
Xue, Meilin
Zhu, Youwei
Xiong, Cheng
Shi, Minmin
Zhao, Shiwei
Shen, Baiyong
Xu, Zhiwei
Jiang, Lingxi
Chen, Hao
author_sort Jiang, Yongsheng
collection PubMed
description BACKGROUND: Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model was established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. RESULTS: Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation and migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC, and it inhibited the secretion of cytokines. According to our TMA panel, high expression of VSIG4 was correlated with fewer infiltration of CD8(+) T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8(+) T cells. HAT inhibitors and knockdown of STAT1 led to decreased expression of VSIG4. CONCLUSIONS: Our data indicate that VSIG4 contributes to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value.
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spelling pubmed-103618812023-07-23 Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma Jiang, Yongsheng Han, Lijie Yang, Jian Yang, Minwei Zhang, Jian Xue, Meilin Zhu, Youwei Xiong, Cheng Shi, Minmin Zhao, Shiwei Shen, Baiyong Xu, Zhiwei Jiang, Lingxi Chen, Hao Cancer Immunol Immunother Research BACKGROUND: Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model was established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. RESULTS: Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation and migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC, and it inhibited the secretion of cytokines. According to our TMA panel, high expression of VSIG4 was correlated with fewer infiltration of CD8(+) T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8(+) T cells. HAT inhibitors and knockdown of STAT1 led to decreased expression of VSIG4. CONCLUSIONS: Our data indicate that VSIG4 contributes to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value. Springer Berlin Heidelberg 2023-04-25 2023 /pmc/articles/PMC10361881/ /pubmed/37097516 http://dx.doi.org/10.1007/s00262-023-03438-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Jiang, Yongsheng
Han, Lijie
Yang, Jian
Yang, Minwei
Zhang, Jian
Xue, Meilin
Zhu, Youwei
Xiong, Cheng
Shi, Minmin
Zhao, Shiwei
Shen, Baiyong
Xu, Zhiwei
Jiang, Lingxi
Chen, Hao
Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
title Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
title_full Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
title_fullStr Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
title_full_unstemmed Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
title_short Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
title_sort identification of a novel immune checkpoint molecule v-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361881/
https://www.ncbi.nlm.nih.gov/pubmed/37097516
http://dx.doi.org/10.1007/s00262-023-03438-y
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