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      m 6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer

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          Abstract

          Background

          The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m 6A) modification in tumor microenvironment (TME) cell infiltration remain unknown.

          Methods

          We comprehensively evaluated the m 6A modification patterns of 1938 gastric cancer samples based on 21 m 6A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m 6A modification patterns of individual tumors using principal component analysis algorithms.

          Results

          Three distinct m 6A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m 6A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits.

          Conclusions

          This work revealed the m 6A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m 6A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.

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          Most cited references13

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          Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade.

          The Cancer Genome Atlas revealed the genomic landscapes of human cancers. In parallel, immunotherapy is transforming the treatment of advanced cancers. Unfortunately, the majority of patients do not respond to immunotherapy, making the identification of predictive markers and the mechanisms of resistance an area of intense research. To increase our understanding of tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers and created The Cancer Immunome Atlas (https://tcia.at/). Cellular characterization of the immune infiltrates showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning, we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts. Our findings and this resource may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.
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            Immunological hallmarks of stromal cells in the tumour microenvironment.

            A dynamic and mutualistic interaction between tumour cells and the surrounding stroma promotes the initiation, progression, metastasis and chemoresistance of solid tumours. Far less understood is the relationship between the stroma and tumour-infiltrating leukocytes; however, emerging evidence suggests that the stromal compartment can shape antitumour immunity and responsiveness to immunotherapy. Thus, there is growing interest in elucidating the immunomodulatory roles of the stroma that evolve within the tumour microenvironment. In this Review, we discuss the evidence that stromal determinants interact with leukocytes and influence antitumour immunity, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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              Mettl3-mediated mRNA m 6 A methylation promotes dendritic cell activation

              N6-methyladenosine (m6A) modification plays important roles in various cellular responses by regulating mRNA biology. However, how m6A modification is involved in innate immunity via affecting the translation of immune transcripts remains to be further investigated. Here we report that RNA methyltransferase Mettl3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function. Specific depletion of Mettl3 in DC resulted in impaired phenotypic and functional maturation of DC, with decreased expression of co-stimulatory molecules CD40, CD80 and cytokine IL-12, and reduced ability to stimulate T cell responses both in vitro and in vivo. Mechanistically, Mettl3-mediated m6A of CD40, CD80 and TLR4 signaling adaptor Tirap transcripts enhanced their translation in DC for stimulating T cell activation, and strengthening TLR4/NF-κB signaling-induced cytokine production. Our findings identify a new role for Mettl3-mediated m6A modification in increasing translation of certain immune transcripts for physiological promotion of DC activation and DC-based T cell response.
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                Author and article information

                Contributors
                wanglei0806@sjtu.edu.cn
                zhouyoulang@ntu.edu.cn
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                12 March 2020
                12 March 2020
                2020
                : 19
                : 53
                Affiliations
                [1 ]GRID grid.440642.0, Research Center of Clinical Medicine, , Affiliated Hospital of Nantong University, ; Nantong, 226001 Jiangsu Province China
                [2 ]GRID grid.260483.b, ISNI 0000 0000 9530 8833, Medical School of Nantong University, ; Nantong, 226001 Jiangsu Province China
                [3 ]GRID grid.440642.0, Department of Cardiothoracic Surgery, , Affiliated Hospital of Nantong University, ; Nantong, 226001 Jiangsu Province China
                [4 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, , Shanghai Jiao Tong University, ; Shanghai, 200240 China
                Article
                1170
                10.1186/s12943-020-01170-0
                7066851
                32164750
                7cb6fca4-ea15-4758-b117-43afcafe5b6f
                © The Author(s) 2020

                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/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 29 October 2019
                : 24 February 2020
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Oncology & Radiotherapy
                m6a,tumor microenvironment,stroma,immunotherapy,mutation burden
                Oncology & Radiotherapy
                m6a, tumor microenvironment, stroma, immunotherapy, mutation burden

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