METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer
The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC...
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| Veröffentlicht in: | Cell death and differentiation 2023-10, Vol.30 (10), p.2265-2279 |
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| creator | Ning, Junya Hou, Xiukun Hao, Jie Zhang, Wei Shi, Yi Huang, Yue Ruan, Xianhui Zheng, Xiangqian Gao, Ming |
| description | The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC. |
| doi_str_mv | 10.1038/s41418-023-01217-x |
| format | Article |
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Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.</description><identifier>ISSN: 1350-9047</identifier><identifier>ISSN: 1476-5403</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-023-01217-x</identifier><identifier>PMID: 37648786</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/109 ; 13/31 ; 13/51 ; 38 ; 38/91 ; 45 ; 45/90 ; 59 ; 631/250/2161 ; 631/337/176 ; 631/67/327 ; 64/60 ; 82/29 ; 82/51 ; Adenosine - analogs & derivatives ; Adenosine - metabolism ; Adenosine - pharmacology ; Animals ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; CD27 Ligand - metabolism ; CD70 antigen ; Cell Biology ; Cell Cycle Analysis ; Cell Line, Tumor ; Demethylation ; Down-regulation ; Drug Resistance, Neoplasm - drug effects ; Extracellular vesicles ; Extracellular Vesicles - metabolism ; Female ; Humans ; Immune checkpoint inhibitors ; Immune Checkpoint Inhibitors - pharmacology ; Immune Checkpoint Inhibitors - therapeutic use ; Immunotherapy ; Life Sciences ; Lymphocytes T ; Macrophages ; Macrophages - drug effects ; Macrophages - immunology ; Macrophages - metabolism ; Male ; Metastases ; Methyltransferases - antagonists & inhibitors ; Methyltransferases - metabolism ; Mice ; Monoclonal antibodies ; N6-methyladenosine ; Papillary thyroid cancer ; PD-1 protein ; Peripheral blood ; Sequence analysis ; Stem Cells ; Thyroid cancer ; Thyroid Cancer, Papillary - drug therapy ; Thyroid Cancer, Papillary - genetics ; Thyroid Cancer, Papillary - immunology ; Thyroid Cancer, Papillary - metabolism ; Thyroid Cancer, Papillary - pathology ; Thyroid Neoplasms - drug therapy ; Thyroid Neoplasms - immunology ; Thyroid Neoplasms - metabolism ; Thyroid Neoplasms - pathology ; Tumor cells ; Tumor microenvironment ; Tumor Microenvironment - drug effects ; Tumors</subject><ispartof>Cell death and differentiation, 2023-10, Vol.30 (10), p.2265-2279</ispartof><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-ed89618a4c4943adcb505f52e7e57dc6722a25bd74641f61cb17dc605cf2b0ad3</citedby><cites>FETCH-LOGICAL-c475t-ed89618a4c4943adcb505f52e7e57dc6722a25bd74641f61cb17dc605cf2b0ad3</cites><orcidid>0000-0002-2743-2247 ; 0000-0002-4104-8284 ; 0000-0001-7922-5007 ; 0000-0003-3049-7532</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589295/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589295/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,41486,42555,51317,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37648786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ning, Junya</creatorcontrib><creatorcontrib>Hou, Xiukun</creatorcontrib><creatorcontrib>Hao, Jie</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Shi, Yi</creatorcontrib><creatorcontrib>Huang, Yue</creatorcontrib><creatorcontrib>Ruan, Xianhui</creatorcontrib><creatorcontrib>Zheng, Xiangqian</creatorcontrib><creatorcontrib>Gao, Ming</creatorcontrib><title>METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.</description><subject>13</subject><subject>13/1</subject><subject>13/109</subject><subject>13/31</subject><subject>13/51</subject><subject>38</subject><subject>38/91</subject><subject>45</subject><subject>45/90</subject><subject>59</subject><subject>631/250/2161</subject><subject>631/337/176</subject><subject>631/67/327</subject><subject>64/60</subject><subject>82/29</subject><subject>82/51</subject><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - metabolism</subject><subject>Adenosine - pharmacology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>CD27 Ligand - metabolism</subject><subject>CD70 antigen</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell Line, Tumor</subject><subject>Demethylation</subject><subject>Down-regulation</subject><subject>Drug Resistance, Neoplasm - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ning, Junya</au><au>Hou, Xiukun</au><au>Hao, Jie</au><au>Zhang, Wei</au><au>Shi, Yi</au><au>Huang, Yue</au><au>Ruan, Xianhui</au><au>Zheng, Xiangqian</au><au>Gao, Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2023-10-01</date><risdate>2023</risdate><volume>30</volume><issue>10</issue><spage>2265</spage><epage>2279</epage><pages>2265-2279</pages><issn>1350-9047</issn><issn>1476-5403</issn><eissn>1476-5403</eissn><abstract>The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>37648786</pmid><doi>10.1038/s41418-023-01217-x</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-2743-2247</orcidid><orcidid>https://orcid.org/0000-0002-4104-8284</orcidid><orcidid>https://orcid.org/0000-0001-7922-5007</orcidid><orcidid>https://orcid.org/0000-0003-3049-7532</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1350-9047 |
| ispartof | Cell death and differentiation, 2023-10, Vol.30 (10), p.2265-2279 |
| issn | 1350-9047 1476-5403 1476-5403 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10589295 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | 13 13/1 13/109 13/31 13/51 38 38/91 45 45/90 59 631/250/2161 631/337/176 631/67/327 64/60 82/29 82/51 Adenosine - analogs & derivatives Adenosine - metabolism Adenosine - pharmacology Animals Apoptosis Biochemistry Biomedical and Life Sciences CD27 Ligand - metabolism CD70 antigen Cell Biology Cell Cycle Analysis Cell Line, Tumor Demethylation Down-regulation Drug Resistance, Neoplasm - drug effects Extracellular vesicles Extracellular Vesicles - metabolism Female Humans Immune checkpoint inhibitors Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunotherapy Life Sciences Lymphocytes T Macrophages Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Male Metastases Methyltransferases - antagonists & inhibitors Methyltransferases - metabolism Mice Monoclonal antibodies N6-methyladenosine Papillary thyroid cancer PD-1 protein Peripheral blood Sequence analysis Stem Cells Thyroid cancer Thyroid Cancer, Papillary - drug therapy Thyroid Cancer, Papillary - genetics Thyroid Cancer, Papillary - immunology Thyroid Cancer, Papillary - metabolism Thyroid Cancer, Papillary - pathology Thyroid Neoplasms - drug therapy Thyroid Neoplasms - immunology Thyroid Neoplasms - metabolism Thyroid Neoplasms - pathology Tumor cells Tumor microenvironment Tumor Microenvironment - drug effects Tumors |
| title | METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T17%3A44%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=METTL3%20inhibition%20induced%20by%20M2%20macrophage-derived%20extracellular%20vesicles%20drives%20anti-PD-1%20therapy%20resistance%20via%20M6A-CD70-mediated%20immune%20suppression%20in%20thyroid%20cancer&rft.jtitle=Cell%20death%20and%20differentiation&rft.au=Ning,%20Junya&rft.date=2023-10-01&rft.volume=30&rft.issue=10&rft.spage=2265&rft.epage=2279&rft.pages=2265-2279&rft.issn=1350-9047&rft.eissn=1476-5403&rft_id=info:doi/10.1038/s41418-023-01217-x&rft_dat=%3Cproquest_pubme%3E2859605226%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2879465545&rft_id=info:pmid/37648786&rfr_iscdi=true |