N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma

Shao-hua Ren,1,2 Ya-fei Qin,1,2 Hong Qin,1,2 Hong-da Wang,1,2 Guang-ming Li,1,2 Yang-lin Zhu,1,2 Cheng-lu Sun,1,2 Bo Shao,1,2 Jing-yi Zhang,1,2 Jing-peng Hao,3 Hao Wang1,2 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Gener...

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Main Authors: Ren SH, Qin YF, Qin H, Wang HD, Li GM, Zhu YL, Sun CL, Shao B, Zhang JY, Hao JP, Wang H
Format: Article
Language:English
Published: Dove Medical Press 2022-03-01
Series:International Journal of General Medicine
Subjects:
Online Access:https://www.dovepress.com/n6-methyladenine-related-signature-for-immune-microenvironment-and-res-peer-reviewed-fulltext-article-IJGM
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author Ren SH
Qin YF
Qin H
Wang HD
Li GM
Zhu YL
Sun CL
Shao B
Zhang JY
Hao JP
Wang H
author_facet Ren SH
Qin YF
Qin H
Wang HD
Li GM
Zhu YL
Sun CL
Shao B
Zhang JY
Hao JP
Wang H
author_sort Ren SH
collection DOAJ
description Shao-hua Ren,1,2 Ya-fei Qin,1,2 Hong Qin,1,2 Hong-da Wang,1,2 Guang-ming Li,1,2 Yang-lin Zhu,1,2 Cheng-lu Sun,1,2 Bo Shao,1,2 Jing-yi Zhang,1,2 Jing-peng Hao,3 Hao Wang1,2 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Hao Wang, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China, Tel/Fax +01186-22-60362502, Email hwangca272@hotmail.comBackground: The prognostic value of m6A-related genes in hepatocellular carcinoma (HCC) and its correlation with the immune microenvironment still requires further investigation.Methods: Consensus clustering by m6A related genes was used to classify 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the m6A related genes model. The International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) datasets were used to verify and evaluate the model. ESTIMATE, CIBERSORTx, the expression levels of immune checkpoint genes, and TIDE were used to investigate the tumor microenvironment (TME) and the response to immunotherapy. Gene set enrichment analyses (GSEA), tumor-associated macrophages (TAMs), and gene-drug sensitivity were also analyzed.Results: By expression value and regression coefficient of five m6A related genes, we constructed the risk score of each patient. The patients with a higher risk score had a considerably poorer prognosis in the primary and validated cohort. For further discussing TME and the response to immunotherapy, we divided the entire set into two groups based on the risk score. Our findings implied that the tumor-infiltrating lymphocytes (TILs) were proportional to the risk scores, which seemed to contradict that patients with higher scores had a poor prognosis. Further, we found that the high-risk group had higher expression of PD-L1, CTLA-4, and PDCD1, indicating immune dysfunction, which may be a fundamental reason for poor prognosis. This was further reinforced by the fact that the low-risk group responded better than the high-risk group to monotherapy and combination therapy.Conclusion: The m6A related risk score is a new independent prognostic factor that correlates with immunotherapy response. It can provide a new therapeutic strategy for improving individual immunotherapy in HCC.Keywords: hepatocellular carcinoma, N6-methyladenine, tumor immune microenvironment, immunotherapy, drug sensitivity
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spelling doaj.art-86728190aff8422ea4a7b8c402ca083f2022-12-21T18:20:30ZengDove Medical PressInternational Journal of General Medicine1178-70742022-03-01Volume 153525354074064N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular CarcinomaRen SHQin YFQin HWang HDLi GMZhu YLSun CLShao BZhang JYHao JPWang HShao-hua Ren,1,2 Ya-fei Qin,1,2 Hong Qin,1,2 Hong-da Wang,1,2 Guang-ming Li,1,2 Yang-lin Zhu,1,2 Cheng-lu Sun,1,2 Bo Shao,1,2 Jing-yi Zhang,1,2 Jing-peng Hao,3 Hao Wang1,2 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Hao Wang, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China, Tel/Fax +01186-22-60362502, Email hwangca272@hotmail.comBackground: The prognostic value of m6A-related genes in hepatocellular carcinoma (HCC) and its correlation with the immune microenvironment still requires further investigation.Methods: Consensus clustering by m6A related genes was used to classify 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the m6A related genes model. The International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) datasets were used to verify and evaluate the model. ESTIMATE, CIBERSORTx, the expression levels of immune checkpoint genes, and TIDE were used to investigate the tumor microenvironment (TME) and the response to immunotherapy. Gene set enrichment analyses (GSEA), tumor-associated macrophages (TAMs), and gene-drug sensitivity were also analyzed.Results: By expression value and regression coefficient of five m6A related genes, we constructed the risk score of each patient. The patients with a higher risk score had a considerably poorer prognosis in the primary and validated cohort. For further discussing TME and the response to immunotherapy, we divided the entire set into two groups based on the risk score. Our findings implied that the tumor-infiltrating lymphocytes (TILs) were proportional to the risk scores, which seemed to contradict that patients with higher scores had a poor prognosis. Further, we found that the high-risk group had higher expression of PD-L1, CTLA-4, and PDCD1, indicating immune dysfunction, which may be a fundamental reason for poor prognosis. This was further reinforced by the fact that the low-risk group responded better than the high-risk group to monotherapy and combination therapy.Conclusion: The m6A related risk score is a new independent prognostic factor that correlates with immunotherapy response. It can provide a new therapeutic strategy for improving individual immunotherapy in HCC.Keywords: hepatocellular carcinoma, N6-methyladenine, tumor immune microenvironment, immunotherapy, drug sensitivityhttps://www.dovepress.com/n6-methyladenine-related-signature-for-immune-microenvironment-and-res-peer-reviewed-fulltext-article-IJGMhepatocellular carcinoman6-methyladeninetumor immune microenvironmentimmunotherapydrug sensitivity
spellingShingle Ren SH
Qin YF
Qin H
Wang HD
Li GM
Zhu YL
Sun CL
Shao B
Zhang JY
Hao JP
Wang H
N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma
International Journal of General Medicine
hepatocellular carcinoma
n6-methyladenine
tumor immune microenvironment
immunotherapy
drug sensitivity
title N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma
title_full N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma
title_fullStr N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma
title_full_unstemmed N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma
title_short N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma
title_sort n6 methyladenine related signature for immune microenvironment and response to immunotherapy in hepatocellular carcinoma
topic hepatocellular carcinoma
n6-methyladenine
tumor immune microenvironment
immunotherapy
drug sensitivity
url https://www.dovepress.com/n6-methyladenine-related-signature-for-immune-microenvironment-and-res-peer-reviewed-fulltext-article-IJGM
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