Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma
Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. T...
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MDPI AG
2023-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/8/2379 |
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| author | Naoshi Nishida Tomoko Aoki Masahiro Morita Hirokazu Chishina Masahiro Takita Hiroshi Ida Satoru Hagiwara Yasunori Minami Kazuomi Ueshima Masatoshi Kudo |
| author_facet | Naoshi Nishida Tomoko Aoki Masahiro Morita Hirokazu Chishina Masahiro Takita Hiroshi Ida Satoru Hagiwara Yasunori Minami Kazuomi Ueshima Masatoshi Kudo |
| author_sort | Naoshi Nishida |
| collection | DOAJ |
| description | Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a “non-inflamed” tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (<i>p</i> = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the “inflamed” group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (<i>p</i> = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the “non-inflamed” tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA. |
| first_indexed | 2024-03-11T05:10:31Z |
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| language | English |
| last_indexed | 2024-03-11T05:10:31Z |
| publishDate | 2023-04-01 |
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| series | Cancers |
| spelling | doaj.art-da735ae2ebb9476093a92967ba1f0de62023-11-17T18:40:09ZengMDPI AGCancers2072-66942023-04-01158237910.3390/cancers15082379Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in CholangiocarcinomaNaoshi Nishida0Tomoko Aoki1Masahiro Morita2Hirokazu Chishina3Masahiro Takita4Hiroshi Ida5Satoru Hagiwara6Yasunori Minami7Kazuomi Ueshima8Masatoshi Kudo9Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanDepartment of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Osaka, JapanCholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a “non-inflamed” tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (<i>p</i> = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the “inflamed” group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (<i>p</i> = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the “non-inflamed” tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA.https://www.mdpi.com/2072-6694/15/8/2379cholangiocarcinomatumor microenvironmentmethylationdownregulationantigen-presenting machineryhuman leukocyte antigen |
| spellingShingle | Naoshi Nishida Tomoko Aoki Masahiro Morita Hirokazu Chishina Masahiro Takita Hiroshi Ida Satoru Hagiwara Yasunori Minami Kazuomi Ueshima Masatoshi Kudo Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma Cancers cholangiocarcinoma tumor microenvironment methylation downregulation antigen-presenting machinery human leukocyte antigen |
| title | Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma |
| title_full | Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma |
| title_fullStr | Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma |
| title_full_unstemmed | Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma |
| title_short | Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma |
| title_sort | non inflamed tumor microenvironment and methylation downregulation of antigen presenting machineries in cholangiocarcinoma |
| topic | cholangiocarcinoma tumor microenvironment methylation downregulation antigen-presenting machinery human leukocyte antigen |
| url | https://www.mdpi.com/2072-6694/15/8/2379 |
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