Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma
Aims Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy. Methods Bulk RNA‐seq and single‐cell RNA‐...
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| Veröffentlicht in: | CNS neuroscience & therapeutics 2024-03, Vol.30 (3), p.e14643-n/a |
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| creator | Wu, Mengwan Shi, Ying Liu, Yuyang Huang, Hongxiang Che, Jiajia Shi, Jing Xu, Chuan |
| description | Aims
Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy.
Methods
Bulk RNA‐seq and single‐cell RNA‐seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co‐culture system. Bone marrow‐derived macrophages (BMDMs) and OT‐II T cells isolated from BALB/c and OT‐II mice respectively were co‐cultured to determine T‐cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses.
Results
Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN‐containing EVs (EVsPDPN) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL‐6, IL‐10, TNF‐α, and TGF‐β1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T‐cell activation.
Conclusions
This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage‐mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.
The schematic diagram illustrates the mechanism of PDPN‐mediated macrophage immunosuppressive polarization. PDPN‐overexpressed GBM cells secrete PDPN‐containing EVs, followed by phagocytosis by unpolarized M0 macrophages, which induce immunosuppressive polarization of macrophages, manifested by the release of immunosuppressive cytokines, ERK phosphorylation activation, diminished MHC II expression, and incompetence to CD4+ T activation. |
| doi_str_mv | 10.1111/cns.14643 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10929222</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A800054995</galeid><sourcerecordid>A800054995</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4713-7c480cd8181e11d6dc266e54c4b2144c2b06479e5917ea505e3879b399262c803</originalsourceid><addsrcrecordid>eNp1kc1u1DAQxyMEoqVw4AVQJC5w2K3t-POEqlX5kCo4AGfLcWa3rmI7xAnQWx-hz8iTMEvKCpCwD7bGv_nPjP9V9ZSSNcV16lNZUy55c686pkqIlTDc3D_cG3JUPSrlihDJtNEPq6NGc0WIkcdVOf-eS47w4-Z2Gl0qMUwTdPWQuzz0LoVUD2OOeYJST3PMI3KulOyD22PR-TEPl263z4_QLdEQ45ygnnIPKOmhRpVdH3LbuzLl6B5XD7auL_Dk7jypPr8-_7R5u7r48Obd5uxi5bmizUp5ronvNNUUKO1k55mUILjnLaOce9YSyZUBYagCJ4iARivTNsYwybwmzUn1atEd5hab85BwxN4OY4huvLbZBfv3SwqXdpe_WkoMM4wxVHhxpzDmLzOUycZQPPT4M5DnYpkRkgqliUT0-T_oVZ7HhPPZhtDGKC4ER2q9UDvXgw1pm7Gwx91BDD4n2AaMn2lCiODGCEx4uSTgR5cywvbQPiV2b75F8-0v85F99ue8B_K32wicLsA3rHL9fyW7ef9xkfwJ6Q--BQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3013974554</pqid></control><display><type>article</type><title>Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma</title><source>MEDLINE</source><source>Wiley-Blackwell Open Access Titles</source><source>DOAJ Directory of Open Access Journals</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Wu, Mengwan ; Shi, Ying ; Liu, Yuyang ; Huang, Hongxiang ; Che, Jiajia ; Shi, Jing ; Xu, Chuan</creator><creatorcontrib>Wu, Mengwan ; Shi, Ying ; Liu, Yuyang ; Huang, Hongxiang ; Che, Jiajia ; Shi, Jing ; Xu, Chuan</creatorcontrib><description>Aims
Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy.
Methods
Bulk RNA‐seq and single‐cell RNA‐seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co‐culture system. Bone marrow‐derived macrophages (BMDMs) and OT‐II T cells isolated from BALB/c and OT‐II mice respectively were co‐cultured to determine T‐cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses.
Results
Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN‐containing EVs (EVsPDPN) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL‐6, IL‐10, TNF‐α, and TGF‐β1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T‐cell activation.
Conclusions
This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage‐mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.
The schematic diagram illustrates the mechanism of PDPN‐mediated macrophage immunosuppressive polarization. PDPN‐overexpressed GBM cells secrete PDPN‐containing EVs, followed by phagocytosis by unpolarized M0 macrophages, which induce immunosuppressive polarization of macrophages, manifested by the release of immunosuppressive cytokines, ERK phosphorylation activation, diminished MHC II expression, and incompetence to CD4+ T activation.</description><identifier>ISSN: 1755-5930</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.14643</identifier><identifier>PMID: 38470096</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Analysis ; Animals ; Antigens ; Bone marrow ; Brain cancer ; Brain tumors ; Cancer therapies ; CD163 antigen ; CD4 antigen ; Cell activation ; Cell culture ; Cytotoxicity ; exosome ; Exosomes - metabolism ; Extracellular vesicles ; GBM ; Gene expression ; Genomes ; Glial fibrillary acidic protein ; Glioblastoma ; Glioblastoma - pathology ; Glioblastoma cells ; Glioblastoma multiforme ; Glioma ; Glioma - metabolism ; Glioma cells ; Humans ; Immune Tolerance ; Immunohistochemistry ; Immunological tolerance ; Immunoregulation ; Immunosuppression ; immunosuppressive TME ; Immunotherapy ; Lymphocytes T ; macrophage ; Macrophages ; Major histocompatibility complex ; Medical prognosis ; Metastases ; Mice ; Original ; PDPN ; Phagocytes ; Ribonucleic acid ; RNA ; RNA sequencing ; T cells ; Therapeutic targets ; Transcription Factors ; Transforming growth factor-b1 ; Tumor necrosis factor-α ; Tumor-Associated Macrophages - metabolism ; Tumor-Associated Macrophages - pathology ; Tumors</subject><ispartof>CNS neuroscience & therapeutics, 2024-03, Vol.30 (3), p.e14643-n/a</ispartof><rights>2024 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.</rights><rights>COPYRIGHT 2024 John Wiley & Sons, Inc.</rights><rights>2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c4713-7c480cd8181e11d6dc266e54c4b2144c2b06479e5917ea505e3879b399262c803</cites><orcidid>0000-0002-5320-2277</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/PMC10929222/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929222/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38470096$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Mengwan</creatorcontrib><creatorcontrib>Shi, Ying</creatorcontrib><creatorcontrib>Liu, Yuyang</creatorcontrib><creatorcontrib>Huang, Hongxiang</creatorcontrib><creatorcontrib>Che, Jiajia</creatorcontrib><creatorcontrib>Shi, Jing</creatorcontrib><creatorcontrib>Xu, Chuan</creatorcontrib><title>Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma</title><title>CNS neuroscience & therapeutics</title><addtitle>CNS Neurosci Ther</addtitle><description>Aims
Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy.
Methods
Bulk RNA‐seq and single‐cell RNA‐seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co‐culture system. Bone marrow‐derived macrophages (BMDMs) and OT‐II T cells isolated from BALB/c and OT‐II mice respectively were co‐cultured to determine T‐cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses.
Results
Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN‐containing EVs (EVsPDPN) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL‐6, IL‐10, TNF‐α, and TGF‐β1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T‐cell activation.
Conclusions
This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage‐mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.
The schematic diagram illustrates the mechanism of PDPN‐mediated macrophage immunosuppressive polarization. PDPN‐overexpressed GBM cells secrete PDPN‐containing EVs, followed by phagocytosis by unpolarized M0 macrophages, which induce immunosuppressive polarization of macrophages, manifested by the release of immunosuppressive cytokines, ERK phosphorylation activation, diminished MHC II expression, and incompetence to CD4+ T activation.</description><subject>Analysis</subject><subject>Animals</subject><subject>Antigens</subject><subject>Bone marrow</subject><subject>Brain cancer</subject><subject>Brain tumors</subject><subject>Cancer therapies</subject><subject>CD163 antigen</subject><subject>CD4 antigen</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cytotoxicity</subject><subject>exosome</subject><subject>Exosomes - metabolism</subject><subject>Extracellular vesicles</subject><subject>GBM</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Glial fibrillary acidic protein</subject><subject>Glioblastoma</subject><subject>Glioblastoma - pathology</subject><subject>Glioblastoma cells</subject><subject>Glioblastoma multiforme</subject><subject>Glioma</subject><subject>Glioma - metabolism</subject><subject>Glioma cells</subject><subject>Humans</subject><subject>Immune Tolerance</subject><subject>Immunohistochemistry</subject><subject>Immunological tolerance</subject><subject>Immunoregulation</subject><subject>Immunosuppression</subject><subject>immunosuppressive TME</subject><subject>Immunotherapy</subject><subject>Lymphocytes T</subject><subject>macrophage</subject><subject>Macrophages</subject><subject>Major histocompatibility complex</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Mice</subject><subject>Original</subject><subject>PDPN</subject><subject>Phagocytes</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA sequencing</subject><subject>T cells</subject><subject>Therapeutic targets</subject><subject>Transcription Factors</subject><subject>Transforming growth factor-b1</subject><subject>Tumor necrosis factor-α</subject><subject>Tumor-Associated Macrophages - metabolism</subject><subject>Tumor-Associated Macrophages - pathology</subject><subject>Tumors</subject><issn>1755-5930</issn><issn>1755-5949</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc1u1DAQxyMEoqVw4AVQJC5w2K3t-POEqlX5kCo4AGfLcWa3rmI7xAnQWx-hz8iTMEvKCpCwD7bGv_nPjP9V9ZSSNcV16lNZUy55c686pkqIlTDc3D_cG3JUPSrlihDJtNEPq6NGc0WIkcdVOf-eS47w4-Z2Gl0qMUwTdPWQuzz0LoVUD2OOeYJST3PMI3KulOyD22PR-TEPl263z4_QLdEQ45ygnnIPKOmhRpVdH3LbuzLl6B5XD7auL_Dk7jypPr8-_7R5u7r48Obd5uxi5bmizUp5ronvNNUUKO1k55mUILjnLaOce9YSyZUBYagCJ4iARivTNsYwybwmzUn1atEd5hab85BwxN4OY4huvLbZBfv3SwqXdpe_WkoMM4wxVHhxpzDmLzOUycZQPPT4M5DnYpkRkgqliUT0-T_oVZ7HhPPZhtDGKC4ER2q9UDvXgw1pm7Gwx91BDD4n2AaMn2lCiODGCEx4uSTgR5cywvbQPiV2b75F8-0v85F99ue8B_K32wicLsA3rHL9fyW7ef9xkfwJ6Q--BQ</recordid><startdate>202403</startdate><enddate>202403</enddate><creator>Wu, Mengwan</creator><creator>Shi, Ying</creator><creator>Liu, Yuyang</creator><creator>Huang, Hongxiang</creator><creator>Che, Jiajia</creator><creator>Shi, Jing</creator><creator>Xu, Chuan</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IAO</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5320-2277</orcidid></search><sort><creationdate>202403</creationdate><title>Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma</title><author>Wu, Mengwan ; Shi, Ying ; Liu, Yuyang ; Huang, Hongxiang ; Che, Jiajia ; Shi, Jing ; Xu, Chuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4713-7c480cd8181e11d6dc266e54c4b2144c2b06479e5917ea505e3879b399262c803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Antigens</topic><topic>Bone marrow</topic><topic>Brain cancer</topic><topic>Brain tumors</topic><topic>Cancer therapies</topic><topic>CD163 antigen</topic><topic>CD4 antigen</topic><topic>Cell activation</topic><topic>Cell culture</topic><topic>Cytotoxicity</topic><topic>exosome</topic><topic>Exosomes - metabolism</topic><topic>Extracellular vesicles</topic><topic>GBM</topic><topic>Gene expression</topic><topic>Genomes</topic><topic>Glial fibrillary acidic protein</topic><topic>Glioblastoma</topic><topic>Glioblastoma - pathology</topic><topic>Glioblastoma cells</topic><topic>Glioblastoma multiforme</topic><topic>Glioma</topic><topic>Glioma - metabolism</topic><topic>Glioma cells</topic><topic>Humans</topic><topic>Immune Tolerance</topic><topic>Immunohistochemistry</topic><topic>Immunological tolerance</topic><topic>Immunoregulation</topic><topic>Immunosuppression</topic><topic>immunosuppressive TME</topic><topic>Immunotherapy</topic><topic>Lymphocytes T</topic><topic>macrophage</topic><topic>Macrophages</topic><topic>Major histocompatibility complex</topic><topic>Medical prognosis</topic><topic>Metastases</topic><topic>Mice</topic><topic>Original</topic><topic>PDPN</topic><topic>Phagocytes</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA sequencing</topic><topic>T cells</topic><topic>Therapeutic targets</topic><topic>Transcription Factors</topic><topic>Transforming growth factor-b1</topic><topic>Tumor necrosis factor-α</topic><topic>Tumor-Associated Macrophages - metabolism</topic><topic>Tumor-Associated Macrophages - pathology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Mengwan</creatorcontrib><creatorcontrib>Shi, Ying</creatorcontrib><creatorcontrib>Liu, Yuyang</creatorcontrib><creatorcontrib>Huang, Hongxiang</creatorcontrib><creatorcontrib>Che, Jiajia</creatorcontrib><creatorcontrib>Shi, Jing</creatorcontrib><creatorcontrib>Xu, Chuan</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale Academic OneFile</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>CNS neuroscience & therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Mengwan</au><au>Shi, Ying</au><au>Liu, Yuyang</au><au>Huang, Hongxiang</au><au>Che, Jiajia</au><au>Shi, Jing</au><au>Xu, Chuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma</atitle><jtitle>CNS neuroscience & therapeutics</jtitle><addtitle>CNS Neurosci Ther</addtitle><date>2024-03</date><risdate>2024</risdate><volume>30</volume><issue>3</issue><spage>e14643</spage><epage>n/a</epage><pages>e14643-n/a</pages><issn>1755-5930</issn><eissn>1755-5949</eissn><abstract>Aims
Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy.
Methods
Bulk RNA‐seq and single‐cell RNA‐seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co‐culture system. Bone marrow‐derived macrophages (BMDMs) and OT‐II T cells isolated from BALB/c and OT‐II mice respectively were co‐cultured to determine T‐cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses.
Results
Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN‐containing EVs (EVsPDPN) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL‐6, IL‐10, TNF‐α, and TGF‐β1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T‐cell activation.
Conclusions
This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage‐mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.
The schematic diagram illustrates the mechanism of PDPN‐mediated macrophage immunosuppressive polarization. PDPN‐overexpressed GBM cells secrete PDPN‐containing EVs, followed by phagocytosis by unpolarized M0 macrophages, which induce immunosuppressive polarization of macrophages, manifested by the release of immunosuppressive cytokines, ERK phosphorylation activation, diminished MHC II expression, and incompetence to CD4+ T activation.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>38470096</pmid><doi>10.1111/cns.14643</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-5320-2277</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley-Blackwell Open Access Titles; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Analysis Animals Antigens Bone marrow Brain cancer Brain tumors Cancer therapies CD163 antigen CD4 antigen Cell activation Cell culture Cytotoxicity exosome Exosomes - metabolism Extracellular vesicles GBM Gene expression Genomes Glial fibrillary acidic protein Glioblastoma Glioblastoma - pathology Glioblastoma cells Glioblastoma multiforme Glioma Glioma - metabolism Glioma cells Humans Immune Tolerance Immunohistochemistry Immunological tolerance Immunoregulation Immunosuppression immunosuppressive TME Immunotherapy Lymphocytes T macrophage Macrophages Major histocompatibility complex Medical prognosis Metastases Mice Original PDPN Phagocytes Ribonucleic acid RNA RNA sequencing T cells Therapeutic targets Transcription Factors Transforming growth factor-b1 Tumor necrosis factor-α Tumor-Associated Macrophages - metabolism Tumor-Associated Macrophages - pathology Tumors |
| title | Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma |
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