SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis
Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription fact...
Gespeichert in:
| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2021-12, Vol.81 (24), p.6131-6141 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 6141 |
|---|---|
| container_issue | 24 |
| container_start_page | 6131 |
| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 81 |
| creator | Yokoyama, Satoru Takahashi, Atsushi Kikuchi, Ryota Nishibu, Soshi Lo, Jennifer A Hejna, Miroslav Moon, Wooyoung M Kato, Shinichiro Zhou, Yue Hodi, F Stephen Song, Jun S Sakurai, Hiroaki Fisher, David E Hayakawa, Yoshihiro |
| description | Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4-IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10-IRF4-IRF1 axis regulated PD-L1 expression independently of JAK-STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10-IRF4-IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. SIGNIFICANCE: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK-STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma. |
| doi_str_mv | 10.1158/0008-5472.CAN-21-2078 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8678351</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2593027686</sourcerecordid><originalsourceid>FETCH-LOGICAL-c529t-17132ddde1ba4e506aff15bd624300777f0f5ecd40349564304d682edec0148c3</originalsourceid><addsrcrecordid>eNpVkF9LwzAUxYMobk4_gtJHXzLzt8lehDKcDtTBVPAtZE3aVdpmNq24b2_K5tCXG-7JuecmPwAuMRpjzOUNQkhCzgQZT5NnSDAkSMgjMMScSigY48dgePAMwJn3H6HlGPFTMKBBk8E4BMnL4h2jaGnzrtSt9dGTLXXtKh3Nq6qrXW7rIi3abdSuG9fl60jX0Xw5YzAUHCXfhT8HJ5kuvb3YnyPwNrt7nT7Ax8X9fJo8wpSTSQuxwJQYYyxeaWY5inWWYb4yMWEUISFEhjJuU8MQZRMeB5GZWBJrbIowkykdgdtd7qZbVdaktm4bXapNU1S62SqnC_X_pi7WKndfSsZCUo5DwPU-oHGfnfWtqgqf2jL817rOK8InFBERyzhY-c6aNs77xmaHNRipHr_q0aoerQr4FcGqxx_mrv6-8TD1y5v-AONVf6k</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2593027686</pqid></control><display><type>article</type><title>SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Yokoyama, Satoru ; Takahashi, Atsushi ; Kikuchi, Ryota ; Nishibu, Soshi ; Lo, Jennifer A ; Hejna, Miroslav ; Moon, Wooyoung M ; Kato, Shinichiro ; Zhou, Yue ; Hodi, F Stephen ; Song, Jun S ; Sakurai, Hiroaki ; Fisher, David E ; Hayakawa, Yoshihiro</creator><creatorcontrib>Yokoyama, Satoru ; Takahashi, Atsushi ; Kikuchi, Ryota ; Nishibu, Soshi ; Lo, Jennifer A ; Hejna, Miroslav ; Moon, Wooyoung M ; Kato, Shinichiro ; Zhou, Yue ; Hodi, F Stephen ; Song, Jun S ; Sakurai, Hiroaki ; Fisher, David E ; Hayakawa, Yoshihiro</creatorcontrib><description>Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4-IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10-IRF4-IRF1 axis regulated PD-L1 expression independently of JAK-STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10-IRF4-IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. SIGNIFICANCE: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK-STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-21-2078</identifier><identifier>PMID: 34728538</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis ; B7-H1 Antigen - antagonists & inhibitors ; B7-H1 Antigen - immunology ; B7-H1 Antigen - metabolism ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cell Proliferation ; Drug Therapy, Combination ; Gene Expression Regulation, Neoplastic ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Immune Checkpoint Inhibitors - pharmacology ; Immunotherapy ; Interferon Regulatory Factor-1 - genetics ; Interferon Regulatory Factor-1 - metabolism ; Interferon Regulatory Factors - genetics ; Interferon Regulatory Factors - metabolism ; Melanoma - drug therapy ; Melanoma - immunology ; Melanoma - metabolism ; Melanoma - pathology ; Mice ; Mice, Inbred C57BL ; Prognosis ; SOXE Transcription Factors - genetics ; SOXE Transcription Factors - metabolism ; Survival Rate ; Tumor Cells, Cultured</subject><ispartof>Cancer research (Chicago, Ill.), 2021-12, Vol.81 (24), p.6131-6141</ispartof><rights>2021 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-17132ddde1ba4e506aff15bd624300777f0f5ecd40349564304d682edec0148c3</citedby><cites>FETCH-LOGICAL-c529t-17132ddde1ba4e506aff15bd624300777f0f5ecd40349564304d682edec0148c3</cites><orcidid>0000-0002-9520-6874 ; 0000-0002-7921-1171 ; 0000-0002-3613-1796 ; 0000-0003-0657-9570</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34728538$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yokoyama, Satoru</creatorcontrib><creatorcontrib>Takahashi, Atsushi</creatorcontrib><creatorcontrib>Kikuchi, Ryota</creatorcontrib><creatorcontrib>Nishibu, Soshi</creatorcontrib><creatorcontrib>Lo, Jennifer A</creatorcontrib><creatorcontrib>Hejna, Miroslav</creatorcontrib><creatorcontrib>Moon, Wooyoung M</creatorcontrib><creatorcontrib>Kato, Shinichiro</creatorcontrib><creatorcontrib>Zhou, Yue</creatorcontrib><creatorcontrib>Hodi, F Stephen</creatorcontrib><creatorcontrib>Song, Jun S</creatorcontrib><creatorcontrib>Sakurai, Hiroaki</creatorcontrib><creatorcontrib>Fisher, David E</creatorcontrib><creatorcontrib>Hayakawa, Yoshihiro</creatorcontrib><title>SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4-IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10-IRF4-IRF1 axis regulated PD-L1 expression independently of JAK-STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10-IRF4-IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. SIGNIFICANCE: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK-STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>B7-H1 Antigen - antagonists & inhibitors</subject><subject>B7-H1 Antigen - immunology</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Proliferation</subject><subject>Drug Therapy, Combination</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Immune Checkpoint Inhibitors - pharmacology</subject><subject>Immunotherapy</subject><subject>Interferon Regulatory Factor-1 - genetics</subject><subject>Interferon Regulatory Factor-1 - metabolism</subject><subject>Interferon Regulatory Factors - genetics</subject><subject>Interferon Regulatory Factors - metabolism</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - immunology</subject><subject>Melanoma - metabolism</subject><subject>Melanoma - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Prognosis</subject><subject>SOXE Transcription Factors - genetics</subject><subject>SOXE Transcription Factors - metabolism</subject><subject>Survival Rate</subject><subject>Tumor Cells, Cultured</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF9LwzAUxYMobk4_gtJHXzLzt8lehDKcDtTBVPAtZE3aVdpmNq24b2_K5tCXG-7JuecmPwAuMRpjzOUNQkhCzgQZT5NnSDAkSMgjMMScSigY48dgePAMwJn3H6HlGPFTMKBBk8E4BMnL4h2jaGnzrtSt9dGTLXXtKh3Nq6qrXW7rIi3abdSuG9fl60jX0Xw5YzAUHCXfhT8HJ5kuvb3YnyPwNrt7nT7Ax8X9fJo8wpSTSQuxwJQYYyxeaWY5inWWYb4yMWEUISFEhjJuU8MQZRMeB5GZWBJrbIowkykdgdtd7qZbVdaktm4bXapNU1S62SqnC_X_pi7WKndfSsZCUo5DwPU-oHGfnfWtqgqf2jL817rOK8InFBERyzhY-c6aNs77xmaHNRipHr_q0aoerQr4FcGqxx_mrv6-8TD1y5v-AONVf6k</recordid><startdate>20211215</startdate><enddate>20211215</enddate><creator>Yokoyama, Satoru</creator><creator>Takahashi, Atsushi</creator><creator>Kikuchi, Ryota</creator><creator>Nishibu, Soshi</creator><creator>Lo, Jennifer A</creator><creator>Hejna, Miroslav</creator><creator>Moon, Wooyoung M</creator><creator>Kato, Shinichiro</creator><creator>Zhou, Yue</creator><creator>Hodi, F Stephen</creator><creator>Song, Jun S</creator><creator>Sakurai, Hiroaki</creator><creator>Fisher, David E</creator><creator>Hayakawa, Yoshihiro</creator><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9520-6874</orcidid><orcidid>https://orcid.org/0000-0002-7921-1171</orcidid><orcidid>https://orcid.org/0000-0002-3613-1796</orcidid><orcidid>https://orcid.org/0000-0003-0657-9570</orcidid></search><sort><creationdate>20211215</creationdate><title>SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis</title><author>Yokoyama, Satoru ; Takahashi, Atsushi ; Kikuchi, Ryota ; Nishibu, Soshi ; Lo, Jennifer A ; Hejna, Miroslav ; Moon, Wooyoung M ; Kato, Shinichiro ; Zhou, Yue ; Hodi, F Stephen ; Song, Jun S ; Sakurai, Hiroaki ; Fisher, David E ; Hayakawa, Yoshihiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-17132ddde1ba4e506aff15bd624300777f0f5ecd40349564304d682edec0148c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>B7-H1 Antigen - antagonists & inhibitors</topic><topic>B7-H1 Antigen - immunology</topic><topic>B7-H1 Antigen - metabolism</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Proliferation</topic><topic>Drug Therapy, Combination</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Immune Checkpoint Inhibitors - pharmacology</topic><topic>Immunotherapy</topic><topic>Interferon Regulatory Factor-1 - genetics</topic><topic>Interferon Regulatory Factor-1 - metabolism</topic><topic>Interferon Regulatory Factors - genetics</topic><topic>Interferon Regulatory Factors - metabolism</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - immunology</topic><topic>Melanoma - metabolism</topic><topic>Melanoma - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Prognosis</topic><topic>SOXE Transcription Factors - genetics</topic><topic>SOXE Transcription Factors - metabolism</topic><topic>Survival Rate</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yokoyama, Satoru</creatorcontrib><creatorcontrib>Takahashi, Atsushi</creatorcontrib><creatorcontrib>Kikuchi, Ryota</creatorcontrib><creatorcontrib>Nishibu, Soshi</creatorcontrib><creatorcontrib>Lo, Jennifer A</creatorcontrib><creatorcontrib>Hejna, Miroslav</creatorcontrib><creatorcontrib>Moon, Wooyoung M</creatorcontrib><creatorcontrib>Kato, Shinichiro</creatorcontrib><creatorcontrib>Zhou, Yue</creatorcontrib><creatorcontrib>Hodi, F Stephen</creatorcontrib><creatorcontrib>Song, Jun S</creatorcontrib><creatorcontrib>Sakurai, Hiroaki</creatorcontrib><creatorcontrib>Fisher, David E</creatorcontrib><creatorcontrib>Hayakawa, Yoshihiro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yokoyama, Satoru</au><au>Takahashi, Atsushi</au><au>Kikuchi, Ryota</au><au>Nishibu, Soshi</au><au>Lo, Jennifer A</au><au>Hejna, Miroslav</au><au>Moon, Wooyoung M</au><au>Kato, Shinichiro</au><au>Zhou, Yue</au><au>Hodi, F Stephen</au><au>Song, Jun S</au><au>Sakurai, Hiroaki</au><au>Fisher, David E</au><au>Hayakawa, Yoshihiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2021-12-15</date><risdate>2021</risdate><volume>81</volume><issue>24</issue><spage>6131</spage><epage>6141</epage><pages>6131-6141</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNγ and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNγ signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4-IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10-IRF4-IRF1 axis regulated PD-L1 expression independently of JAK-STAT pathway activity, and suppression of SOX10 increased the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10-IRF4-IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. SIGNIFICANCE: This study identifies a novel SOX10/IRF4 pathway that regulates noncanonical induction of IRF1 independent of the JAK-STAT pathway and can be targeted to improve the efficacy of anti-PD-1 therapy in melanoma.</abstract><cop>United States</cop><pmid>34728538</pmid><doi>10.1158/0008-5472.CAN-21-2078</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-9520-6874</orcidid><orcidid>https://orcid.org/0000-0002-7921-1171</orcidid><orcidid>https://orcid.org/0000-0002-3613-1796</orcidid><orcidid>https://orcid.org/0000-0003-0657-9570</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2021-12, Vol.81 (24), p.6131-6141 |
| issn | 0008-5472 1538-7445 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8678351 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Apoptosis B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - immunology B7-H1 Antigen - metabolism Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cell Proliferation Drug Therapy, Combination Gene Expression Regulation, Neoplastic Histone Deacetylase Inhibitors - pharmacology Humans Immune Checkpoint Inhibitors - pharmacology Immunotherapy Interferon Regulatory Factor-1 - genetics Interferon Regulatory Factor-1 - metabolism Interferon Regulatory Factors - genetics Interferon Regulatory Factors - metabolism Melanoma - drug therapy Melanoma - immunology Melanoma - metabolism Melanoma - pathology Mice Mice, Inbred C57BL Prognosis SOXE Transcription Factors - genetics SOXE Transcription Factors - metabolism Survival Rate Tumor Cells, Cultured |
| title | SOX10 Regulates Melanoma Immunogenicity through an IRF4-IRF1 Axis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T21%3A16%3A01IST&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=SOX10%20Regulates%20Melanoma%20Immunogenicity%20through%20an%20IRF4-IRF1%20Axis&rft.jtitle=Cancer%20research%20(Chicago,%20Ill.)&rft.au=Yokoyama,%20Satoru&rft.date=2021-12-15&rft.volume=81&rft.issue=24&rft.spage=6131&rft.epage=6141&rft.pages=6131-6141&rft.issn=0008-5472&rft.eissn=1538-7445&rft_id=info:doi/10.1158/0008-5472.CAN-21-2078&rft_dat=%3Cproquest_pubme%3E2593027686%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=2593027686&rft_id=info:pmid/34728538&rfr_iscdi=true |