Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells

Abstract Background A new strategy, particularly a novel combination, for immunotherapy in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to be formulated. Studies on the interferon-γ (IFN-γ)/ Janus kinase (JAK)/ signal transducer and activator of transcription (STAT)1 pat...

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Autores principales:	Yi-Hsin Liang, Kuo-Hsing Chen, Jia-Huei Tsai, Yung-Ming Cheng, Chang-Cheng Lee, Chiu-Hwa Kao, Kuang-Yu Chan, Yeh-Ting Chen, Wen-Ling Hsu, Kun-Huei Yeh
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Colorectal cancer Major histocompatibility complex (MHC) class I Proteasome inhibitors STAT1 Tumor infiltrating lymphocytes (TILs) Interferon-γ (IFN-γ) Medicine R
Acceso en línea:	https://doaj.org/article/e4791b98016445cf8bb98b0578157f13
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spelling	oai:doaj.org-article:e4791b98016445cf8bb98b0578157f132021-11-14T12:16:02ZProteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells10.1186/s12929-021-00769-91423-0127https://doaj.org/article/e4791b98016445cf8bb98b0578157f132021-11-01T00:00:00Zhttps://doi.org/10.1186/s12929-021-00769-9https://doaj.org/toc/1423-0127Abstract Background A new strategy, particularly a novel combination, for immunotherapy in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to be formulated. Studies on the interferon-γ (IFN-γ)/ Janus kinase (JAK)/ signal transducer and activator of transcription (STAT)1 pathway provide new directions in this regard. Methods Our study applies three colon cancer cell lines, including microsatellite stable (MSS) cell lines, which are SW480 and SW620, and microsatellite instability-high (MSI-H) cell line, which is DLD-1. We compared the expressions of immune surface markers on colon cancer cells in response to IFN-γ. We elucidated these mechanisms, which involved the upregulation of immune surface markers. Furthermore, we examined real-world clinical samples using the PerkinElmer Opal multiplex system and NanoString analysis. Results We established that the baseline expression of major histocompatibility complex (MHC) class I alleles and programmed death-ligand 1 (PD-L1) were generally low in cell line models. The immune surface markers were significantly increased after IFN-γ stimulation on SW480 but were notably unresponsive on the SW620 cell line. We discovered that STAT1 and phosphorylated STAT1 (pSTAT1) were downregulated in the SW620 cell line. We verified that the STAT1/pSTAT1 could be restored through the application of proteasome inhibitors, especially bortezomib. The expression of MHC class I as downstream signals of STAT1 was also up-regulated by proteasome inhibitors. The similar results were reproduced in DLD-1 cell line, which was also initially unresponsive to IFN-γ. In real-world samples of patients with mCRC, we found that higher STAT1 expression in tumor cells was strongly indicative of a highly immunogenic microenvironment, with significantly higher expression levels of MHC class I and PD-L1, not only on tumor cells but also on non-tumor cells. Furthermore, tumor infiltrating lymphocytes (TILs) were increased in the positive-STAT1 group. Through NanoString analysis, we confirmed that the mRNA expressions of IFN-γ, human leukocyte antigen (HLA)-A, HLA-E, and HLA-G were also significantly higher in the positive-STAT1 group than those in the negative-STAT1 group. Conclusion Our study provides a novel rationale for the addition of bortezomib, a proteasome inhibitor, into new immunotherapy combinations.Yi-Hsin LiangKuo-Hsing ChenJia-Huei TsaiYung-Ming ChengChang-Cheng LeeChiu-Hwa KaoKuang-Yu ChanYeh-Ting ChenWen-Ling HsuKun-Huei YehBMCarticleColorectal cancerMajor histocompatibility complex (MHC) class IProteasome inhibitorsSTAT1Tumor infiltrating lymphocytes (TILs)Interferon-γ (IFN-γ)MedicineRENJournal of Biomedical Science, Vol 28, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Colorectal cancer Major histocompatibility complex (MHC) class I Proteasome inhibitors STAT1 Tumor infiltrating lymphocytes (TILs) Interferon-γ (IFN-γ) Medicine R
spellingShingle	Colorectal cancer Major histocompatibility complex (MHC) class I Proteasome inhibitors STAT1 Tumor infiltrating lymphocytes (TILs) Interferon-γ (IFN-γ) Medicine R Yi-Hsin Liang Kuo-Hsing Chen Jia-Huei Tsai Yung-Ming Cheng Chang-Cheng Lee Chiu-Hwa Kao Kuang-Yu Chan Yeh-Ting Chen Wen-Ling Hsu Kun-Huei Yeh Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells
description	Abstract Background A new strategy, particularly a novel combination, for immunotherapy in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to be formulated. Studies on the interferon-γ (IFN-γ)/ Janus kinase (JAK)/ signal transducer and activator of transcription (STAT)1 pathway provide new directions in this regard. Methods Our study applies three colon cancer cell lines, including microsatellite stable (MSS) cell lines, which are SW480 and SW620, and microsatellite instability-high (MSI-H) cell line, which is DLD-1. We compared the expressions of immune surface markers on colon cancer cells in response to IFN-γ. We elucidated these mechanisms, which involved the upregulation of immune surface markers. Furthermore, we examined real-world clinical samples using the PerkinElmer Opal multiplex system and NanoString analysis. Results We established that the baseline expression of major histocompatibility complex (MHC) class I alleles and programmed death-ligand 1 (PD-L1) were generally low in cell line models. The immune surface markers were significantly increased after IFN-γ stimulation on SW480 but were notably unresponsive on the SW620 cell line. We discovered that STAT1 and phosphorylated STAT1 (pSTAT1) were downregulated in the SW620 cell line. We verified that the STAT1/pSTAT1 could be restored through the application of proteasome inhibitors, especially bortezomib. The expression of MHC class I as downstream signals of STAT1 was also up-regulated by proteasome inhibitors. The similar results were reproduced in DLD-1 cell line, which was also initially unresponsive to IFN-γ. In real-world samples of patients with mCRC, we found that higher STAT1 expression in tumor cells was strongly indicative of a highly immunogenic microenvironment, with significantly higher expression levels of MHC class I and PD-L1, not only on tumor cells but also on non-tumor cells. Furthermore, tumor infiltrating lymphocytes (TILs) were increased in the positive-STAT1 group. Through NanoString analysis, we confirmed that the mRNA expressions of IFN-γ, human leukocyte antigen (HLA)-A, HLA-E, and HLA-G were also significantly higher in the positive-STAT1 group than those in the negative-STAT1 group. Conclusion Our study provides a novel rationale for the addition of bortezomib, a proteasome inhibitor, into new immunotherapy combinations.
format	article
author	Yi-Hsin Liang Kuo-Hsing Chen Jia-Huei Tsai Yung-Ming Cheng Chang-Cheng Lee Chiu-Hwa Kao Kuang-Yu Chan Yeh-Ting Chen Wen-Ling Hsu Kun-Huei Yeh
author_facet	Yi-Hsin Liang Kuo-Hsing Chen Jia-Huei Tsai Yung-Ming Cheng Chang-Cheng Lee Chiu-Hwa Kao Kuang-Yu Chan Yeh-Ting Chen Wen-Ling Hsu Kun-Huei Yeh
author_sort	Yi-Hsin Liang
title	Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells
title_short	Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells
title_full	Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells
title_fullStr	Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells
title_full_unstemmed	Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells
title_sort	proteasome inhibitors restore the stat1 pathway and enhance the expression of mhc class i on human colon cancer cells
publisher	BMC
publishDate	2021
url	https://doaj.org/article/e4791b98016445cf8bb98b0578157f13
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Proteasome inhibitors restore the STAT1 pathway and enhance the expression of MHC class I on human colon cancer cells

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