Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment
BackgroundTo determine the role of N6-methyladenosine (m6A) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD).MethodsConsensus clustering was performed to identify the subgroups with distinct immune or m6A modification patterns usi...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1514497/full |
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| author | Quan Chen Quan Chen Weijun Wan Qing Zhao Juan Li Juan Li Yanli Xiong Yanli Xiong Yuchuan Yuan Lu Tang Xiaofeng Wu Wei Xing Wei Guo Di Lu Luoquan Ao Xiang Xu Xiang Xu Xiang Xu Xiang Ao Xiang Ao Xiang Ao |
| author_facet | Quan Chen Quan Chen Weijun Wan Qing Zhao Juan Li Juan Li Yanli Xiong Yanli Xiong Yuchuan Yuan Lu Tang Xiaofeng Wu Wei Xing Wei Guo Di Lu Luoquan Ao Xiang Xu Xiang Xu Xiang Xu Xiang Ao Xiang Ao Xiang Ao |
| author_sort | Quan Chen |
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| description | BackgroundTo determine the role of N6-methyladenosine (m6A) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD).MethodsConsensus clustering was performed to identify the subgroups with distinct immune or m6A modification patterns using profiles from TCGA. A risk score model was constructed using least absolute shrinkage and selection operator regression and validated in two independent cohorts and LUAD tissue microarrays. For experimental validation, the regulation of METTL3/m6A axis in the expression of candidate genes by RIP-qPCR assay in A549 and H460 cell lines. Co-culture experiments with human T cells were performed to evaluate the impact of METTL3 on the enhancement of anti-tumor immunity through in vitro experiments.ResultsWe identified 282 m6A regulator genes and 955 immune-related genes, selecting seven key genes (SFTPC, CYP24A1, KRT6A, PTTG1, S100P, FAM83A, and ANLN) to develop a risk score model using Lasso regression. High-risk patients, determined by this model, exhibited poorer prognosis, increased immune infiltration, higher tumor mutational burden, more neoantigens, and elevated PD-L1 expression. These findings were validated by two independent databases and LUAD tissue microarrays. METTL3 was found to impact the mRNA expression of these genes, with METTL3 deficiency abolishing these interactions. Inhibition of METTL3 enhanced anti-tumor immunity, T cell activation, exhaustion, and infiltration in vitro.ConclusionThis risk score system shows promise for prognostic prediction and the development of personalized treatment strategies for LUAD patients. |
| format | Article |
| id | doaj-art-4cc2885ffc3b4bbd9c39c6398f59b9b0 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-4cc2885ffc3b4bbd9c39c6398f59b9b02025-08-20T02:22:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-12-011510.3389/fimmu.2024.15144971514497Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironmentQuan Chen0Quan Chen1Weijun Wan2Qing Zhao3Juan Li4Juan Li5Yanli Xiong6Yanli Xiong7Yuchuan Yuan8Lu Tang9Xiaofeng Wu10Wei Xing11Wei Guo12Di Lu13Luoquan Ao14Xiang Xu15Xiang Xu16Xiang Xu17Xiang Ao18Xiang Ao19Xiang Ao20State Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaYunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaCancer Center, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaCancer Center, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaYunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaYunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University, Chongqing, ChinaState Key Laboratory of Trauma and Chemical Poisoning, Department of Stem Cell and Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, ChinaDepartment of orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse, ChinaInstitute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, ChinaBackgroundTo determine the role of N6-methyladenosine (m6A) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD).MethodsConsensus clustering was performed to identify the subgroups with distinct immune or m6A modification patterns using profiles from TCGA. A risk score model was constructed using least absolute shrinkage and selection operator regression and validated in two independent cohorts and LUAD tissue microarrays. For experimental validation, the regulation of METTL3/m6A axis in the expression of candidate genes by RIP-qPCR assay in A549 and H460 cell lines. Co-culture experiments with human T cells were performed to evaluate the impact of METTL3 on the enhancement of anti-tumor immunity through in vitro experiments.ResultsWe identified 282 m6A regulator genes and 955 immune-related genes, selecting seven key genes (SFTPC, CYP24A1, KRT6A, PTTG1, S100P, FAM83A, and ANLN) to develop a risk score model using Lasso regression. High-risk patients, determined by this model, exhibited poorer prognosis, increased immune infiltration, higher tumor mutational burden, more neoantigens, and elevated PD-L1 expression. These findings were validated by two independent databases and LUAD tissue microarrays. METTL3 was found to impact the mRNA expression of these genes, with METTL3 deficiency abolishing these interactions. Inhibition of METTL3 enhanced anti-tumor immunity, T cell activation, exhaustion, and infiltration in vitro.ConclusionThis risk score system shows promise for prognostic prediction and the development of personalized treatment strategies for LUAD patients.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1514497/fulllung adenocarcinomaN6-methyladenosine modificationtumor immune microenvironmentprognosispredictive modelmulti-omics validation |
| spellingShingle | Quan Chen Quan Chen Weijun Wan Qing Zhao Juan Li Juan Li Yanli Xiong Yanli Xiong Yuchuan Yuan Lu Tang Xiaofeng Wu Wei Xing Wei Guo Di Lu Luoquan Ao Xiang Xu Xiang Xu Xiang Xu Xiang Ao Xiang Ao Xiang Ao Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment Frontiers in Immunology lung adenocarcinoma N6-methyladenosine modification tumor immune microenvironment prognosis predictive model multi-omics validation |
| title | Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment |
| title_full | Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment |
| title_fullStr | Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment |
| title_full_unstemmed | Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment |
| title_short | Decoding the prognostic landscape of LUAD: the interplay between N6-methyladenosine modification and immune microenvironment |
| title_sort | decoding the prognostic landscape of luad the interplay between n6 methyladenosine modification and immune microenvironment |
| topic | lung adenocarcinoma N6-methyladenosine modification tumor immune microenvironment prognosis predictive model multi-omics validation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1514497/full |
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