Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy
ABSTRACT Background Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) t...
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Wiley
2024-11-01
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| Online Access: | https://doi.org/10.1002/ctm2.70089 |
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| author | Kaixin Wu Sa Li Guangliang Hong Hongzhi Dong Tongke Tang He Liu Lingmei Jin Siyuan Lin Jingyun Ji Mingli Hu Shuntian Chen Haoyuan Wu Guanzheng Luo Haoyuan Wu Xiangqian Kong Jiekai Chen Jiangping He Hongling Wu |
| author_facet | Kaixin Wu Sa Li Guangliang Hong Hongzhi Dong Tongke Tang He Liu Lingmei Jin Siyuan Lin Jingyun Ji Mingli Hu Shuntian Chen Haoyuan Wu Guanzheng Luo Haoyuan Wu Xiangqian Kong Jiekai Chen Jiangping He Hongling Wu |
| author_sort | Kaixin Wu |
| collection | DOAJ |
| description | ABSTRACT Background Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6‐methyladenosine (m6A) is known to be involved in tumourigenesis. However, the role of m6A in regulating T‐cell function and enhancing anti‐tumour immunity remains unexplored. Methods Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m6A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA‐seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single‐cell RNA‐seq (scRNA‐seq). Furthermore, in vitro and in vivo T‐cell cytotoxicity killing assay and CRISPR Cas9‐mediated m6A reader YTHDF1‐3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m6A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells. Results We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T‐cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti‐tumour immune response, along with deletion of the m6A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)‐I degradation. Remarkably, these anti‐tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon‐gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T‐cell killing ability, and concurrently dampening the expression of exhaustion‐related genes. Conclusion Targeting METTL3 enhances anti‐tumour immunity by boosting T‐cell cytotoxicity and reversing T‐cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti‐tumour defenses and overcome immune resistance. Key points Targeting METTL3 augments tumour cell immunogenicity and sustains T‐cell function. T cell with METTL3 inhibition can reverse T‐cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti‐PD‐1 therapy. YTHDF2 deletion in tumours prolong the lifespan of MHC‐I mRNAs. |
| format | Article |
| id | doaj-art-a3af5784d3174183b4c024daae7e711b |
| institution | Kabale University |
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| language | English |
| publishDate | 2024-11-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-a3af5784d3174183b4c024daae7e711b2024-12-05T05:48:39ZengWileyClinical and Translational Medicine2001-13262024-11-011411n/an/a10.1002/ctm2.70089Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapyKaixin Wu0Sa Li1Guangliang Hong2Hongzhi Dong3Tongke Tang4He Liu5Lingmei Jin6Siyuan Lin7Jingyun Ji8Mingli Hu9Shuntian Chen10Haoyuan Wu11Guanzheng Luo12Haoyuan Wu13Xiangqian Kong14Jiekai Chen15Jiangping He16Hongling Wu17Center for Cell Lineage and Atlas Bioland Laboratory, Guangzhou Regenerative Medicine and Health GuangDong Laboratory Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaGuangzhou National Laboratory Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaCenter for Cell Lineage and Atlas Bioland Laboratory, Guangzhou Regenerative Medicine and Health GuangDong Laboratory Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaGuangzhou National Laboratory Guangzhou ChinaMOE Key Laboratory of Gene Function and Regulation Guangdong Province Key Laboratory of Pharmaceutical Functional Genes State Key Laboratory of Biocontrol School of Life Sciences Sun Yat‐Sen University Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaJoint School of Life Sciences Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou Medical University Guangzhou ChinaJoint School of Life Sciences Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou Medical University Guangzhou ChinaMOE Key Laboratory of Gene Function and Regulation Guangdong Province Key Laboratory of Pharmaceutical Functional Genes State Key Laboratory of Biocontrol School of Life Sciences Sun Yat‐Sen University Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaCenter for Cell Lineage and Atlas Bioland Laboratory, Guangzhou Regenerative Medicine and Health GuangDong Laboratory Guangzhou ChinaThe Fifth Affiliated Hospital of Guangzhou Medical University Guangzhou ChinaCenter for Cell Lineage and Development Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou ChinaABSTRACT Background Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6‐methyladenosine (m6A) is known to be involved in tumourigenesis. However, the role of m6A in regulating T‐cell function and enhancing anti‐tumour immunity remains unexplored. Methods Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m6A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA‐seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single‐cell RNA‐seq (scRNA‐seq). Furthermore, in vitro and in vivo T‐cell cytotoxicity killing assay and CRISPR Cas9‐mediated m6A reader YTHDF1‐3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m6A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells. Results We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T‐cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti‐tumour immune response, along with deletion of the m6A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)‐I degradation. Remarkably, these anti‐tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon‐gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T‐cell killing ability, and concurrently dampening the expression of exhaustion‐related genes. Conclusion Targeting METTL3 enhances anti‐tumour immunity by boosting T‐cell cytotoxicity and reversing T‐cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti‐tumour defenses and overcome immune resistance. Key points Targeting METTL3 augments tumour cell immunogenicity and sustains T‐cell function. T cell with METTL3 inhibition can reverse T‐cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti‐PD‐1 therapy. YTHDF2 deletion in tumours prolong the lifespan of MHC‐I mRNAs.https://doi.org/10.1002/ctm2.70089B16 melanomaimmunotherapyMETTL3N6‐methyladenosine (m6A)T‐cell functionYTHDF2 |
| spellingShingle | Kaixin Wu Sa Li Guangliang Hong Hongzhi Dong Tongke Tang He Liu Lingmei Jin Siyuan Lin Jingyun Ji Mingli Hu Shuntian Chen Haoyuan Wu Guanzheng Luo Haoyuan Wu Xiangqian Kong Jiekai Chen Jiangping He Hongling Wu Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy Clinical and Translational Medicine B16 melanoma immunotherapy METTL3 N6‐methyladenosine (m6A) T‐cell function YTHDF2 |
| title | Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy |
| title_full | Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy |
| title_fullStr | Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy |
| title_full_unstemmed | Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy |
| title_short | Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy |
| title_sort | targeting mettl3 as a checkpoint to enhance t cells for tumour immunotherapy |
| topic | B16 melanoma immunotherapy METTL3 N6‐methyladenosine (m6A) T‐cell function YTHDF2 |
| url | https://doi.org/10.1002/ctm2.70089 |
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