Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy
Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcri...
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| Veröffentlicht in: | Oncogene 2018-09, Vol.37 (36), p.4941-4954 |
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| creator | Zhu, Bo Tang, Liming Chen, Shuyang Yin, Chengqian Peng, Shiguang Li, Xin Liu, Tongzheng Liu, Wei Han, Changpeng Stawski, Lukasz Xu, Zhi-Xiang Zhou, Guangbiao Chen, Xiang Gao, Xiumei Goding, Colin R. Xu, Nan Cui, Rutao Cao, Peng |
| description | Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1)
as
an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8
+
and CD4
+
T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment. |
| doi_str_mv | 10.1038/s41388-018-0314-0 |
| format | Article |
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as
an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8
+
and CD4
+
T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-018-0314-0</identifier><identifier>PMID: 29786078</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/105 ; 13/109 ; 13/21 ; 13/31 ; 13/44 ; 13/51 ; 13/89 ; 13/95 ; 38/1 ; 631/67/1813/1634 ; 631/80 ; 82/51 ; Animals ; Antibodies ; Antineoplastic agents ; Antitumor activity ; Apoptosis ; B7-H1 Antigen - metabolism ; Biochemistry ; Biopharmaceuticals ; Cancer treatment ; CD4 antigen ; CD8 antigen ; Cell Biology ; Cell death ; Cell Line, Tumor ; Female ; Gene expression ; HEK293 Cells ; Human Genetics ; Humans ; Immune checkpoint ; Immune response ; Internal Medicine ; Lymphocytes T ; Medical schools ; Medicine ; Medicine & Public Health ; Melanoma ; Melanoma - metabolism ; Metastases ; Mice ; Mice, Inbred C57BL ; Oncology ; PD-1 protein ; PD-L1 protein ; Radiation (Physics) ; Retirement benefits ; Signal Transduction - physiology ; Skin ; T cells ; Transcription (Genetics) ; Transcription, Genetic - physiology ; Transcriptional Activation - physiology ; Transcriptional coactivators ; Tumors ; Ultraviolet radiation</subject><ispartof>Oncogene, 2018-09, Vol.37 (36), p.4941-4954</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c548t-1ed85e9878618ea15315614735af839c676af25c462595d9daa7f20db7e4c77c3</citedby><cites>FETCH-LOGICAL-c548t-1ed85e9878618ea15315614735af839c676af25c462595d9daa7f20db7e4c77c3</cites><orcidid>0000-0003-4247-6245</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-018-0314-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-018-0314-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29786078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Bo</creatorcontrib><creatorcontrib>Tang, Liming</creatorcontrib><creatorcontrib>Chen, Shuyang</creatorcontrib><creatorcontrib>Yin, Chengqian</creatorcontrib><creatorcontrib>Peng, Shiguang</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Liu, Tongzheng</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>Han, Changpeng</creatorcontrib><creatorcontrib>Stawski, Lukasz</creatorcontrib><creatorcontrib>Xu, Zhi-Xiang</creatorcontrib><creatorcontrib>Zhou, Guangbiao</creatorcontrib><creatorcontrib>Chen, Xiang</creatorcontrib><creatorcontrib>Gao, Xiumei</creatorcontrib><creatorcontrib>Goding, Colin R.</creatorcontrib><creatorcontrib>Xu, Nan</creatorcontrib><creatorcontrib>Cui, Rutao</creatorcontrib><creatorcontrib>Cao, Peng</creatorcontrib><title>Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1)
as
an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8
+
and CD4
+
T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.</description><subject>13/1</subject><subject>13/105</subject><subject>13/109</subject><subject>13/21</subject><subject>13/31</subject><subject>13/44</subject><subject>13/51</subject><subject>13/89</subject><subject>13/95</subject><subject>38/1</subject><subject>631/67/1813/1634</subject><subject>631/80</subject><subject>82/51</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antineoplastic agents</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Biochemistry</subject><subject>Biopharmaceuticals</subject><subject>Cancer treatment</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Female</subject><subject>Gene expression</subject><subject>HEK293 Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immune checkpoint</subject><subject>Immune response</subject><subject>Internal Medicine</subject><subject>Lymphocytes T</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Melanoma</subject><subject>Melanoma - metabolism</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Oncology</subject><subject>PD-1 protein</subject><subject>PD-L1 protein</subject><subject>Radiation (Physics)</subject><subject>Retirement benefits</subject><subject>Signal Transduction - physiology</subject><subject>Skin</subject><subject>T cells</subject><subject>Transcription (Genetics)</subject><subject>Transcription, Genetic - physiology</subject><subject>Transcriptional Activation - physiology</subject><subject>Transcriptional coactivators</subject><subject>Tumors</subject><subject>Ultraviolet radiation</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kU1rFTEYhYMo9lr9AW4k4MbN1HxMJsmy1E-4oIu6Dm8z70xTZibXJCPcf2-GWy2KEkIgec6bcziEvOTsgjNp3uaWS2MaxuuWvG3YI7Ljre4apWz7mOyYVayxQooz8iznO8aYtkw8JWfCatMxbXbk9hrSiCUsIy23SNdDLglhpiXBkn0KhxLiAhMFX8IPKDHRONCv75o9p5ApLBSmgmmB-oq0aqHgeKRhoTNOsMQZtrEJDsfn5MkAU8YX9-c5-fbh_fXVp2b_5ePnq8t941VrSsOxNwqtqf64QeBKctXVTFLBYKT1ne5gEMq3nVBW9bYH0INg_Y3G1mvt5Tl5c5p7SPH7irm4OWSPU3WDcc1OsFZoJTvLKvr6L_QurjXLVCnOmFSy_vhAjTChC8sQa0q_DXWXSgtjheh4pS7-QdXV4xx8XHAI9f4PAT8JfIo5JxzcIYUZ0tFx5rZ23aldV9t1W7tuM_zq3vB6M2P_W_GrzgqIE5Dr0zJiekj0_6k_AZr5rac</recordid><startdate>201809</startdate><enddate>201809</enddate><creator>Zhu, Bo</creator><creator>Tang, Liming</creator><creator>Chen, Shuyang</creator><creator>Yin, Chengqian</creator><creator>Peng, Shiguang</creator><creator>Li, Xin</creator><creator>Liu, Tongzheng</creator><creator>Liu, Wei</creator><creator>Han, Changpeng</creator><creator>Stawski, Lukasz</creator><creator>Xu, Zhi-Xiang</creator><creator>Zhou, Guangbiao</creator><creator>Chen, Xiang</creator><creator>Gao, Xiumei</creator><creator>Goding, Colin R.</creator><creator>Xu, Nan</creator><creator>Cui, Rutao</creator><creator>Cao, Peng</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</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>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4247-6245</orcidid></search><sort><creationdate>201809</creationdate><title>Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy</title><author>Zhu, Bo ; Tang, Liming ; Chen, Shuyang ; Yin, Chengqian ; Peng, Shiguang ; Li, Xin ; Liu, Tongzheng ; Liu, Wei ; Han, Changpeng ; Stawski, Lukasz ; Xu, Zhi-Xiang ; Zhou, Guangbiao ; Chen, Xiang ; Gao, Xiumei ; Goding, Colin R. ; Xu, Nan ; Cui, Rutao ; Cao, Peng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c548t-1ed85e9878618ea15315614735af839c676af25c462595d9daa7f20db7e4c77c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13/1</topic><topic>13/105</topic><topic>13/109</topic><topic>13/21</topic><topic>13/31</topic><topic>13/44</topic><topic>13/51</topic><topic>13/89</topic><topic>13/95</topic><topic>38/1</topic><topic>631/67/1813/1634</topic><topic>631/80</topic><topic>82/51</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antineoplastic agents</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>B7-H1 Antigen - metabolism</topic><topic>Biochemistry</topic><topic>Biopharmaceuticals</topic><topic>Cancer treatment</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell Biology</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Female</topic><topic>Gene expression</topic><topic>HEK293 Cells</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immune checkpoint</topic><topic>Immune response</topic><topic>Internal Medicine</topic><topic>Lymphocytes T</topic><topic>Medical schools</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Melanoma</topic><topic>Melanoma - metabolism</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Oncology</topic><topic>PD-1 protein</topic><topic>PD-L1 protein</topic><topic>Radiation (Physics)</topic><topic>Retirement benefits</topic><topic>Signal Transduction - physiology</topic><topic>Skin</topic><topic>T cells</topic><topic>Transcription (Genetics)</topic><topic>Transcription, Genetic - 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Bo</au><au>Tang, Liming</au><au>Chen, Shuyang</au><au>Yin, Chengqian</au><au>Peng, Shiguang</au><au>Li, Xin</au><au>Liu, Tongzheng</au><au>Liu, Wei</au><au>Han, Changpeng</au><au>Stawski, Lukasz</au><au>Xu, Zhi-Xiang</au><au>Zhou, Guangbiao</au><au>Chen, Xiang</au><au>Gao, Xiumei</au><au>Goding, Colin R.</au><au>Xu, Nan</au><au>Cui, Rutao</au><au>Cao, Peng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2018-09</date><risdate>2018</risdate><volume>37</volume><issue>36</issue><spage>4941</spage><epage>4954</epage><pages>4941-4954</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1)
as
an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8
+
and CD4
+
T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29786078</pmid><doi>10.1038/s41388-018-0314-0</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-4247-6245</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 13/1 13/105 13/109 13/21 13/31 13/44 13/51 13/89 13/95 38/1 631/67/1813/1634 631/80 82/51 Animals Antibodies Antineoplastic agents Antitumor activity Apoptosis B7-H1 Antigen - metabolism Biochemistry Biopharmaceuticals Cancer treatment CD4 antigen CD8 antigen Cell Biology Cell death Cell Line, Tumor Female Gene expression HEK293 Cells Human Genetics Humans Immune checkpoint Immune response Internal Medicine Lymphocytes T Medical schools Medicine Medicine & Public Health Melanoma Melanoma - metabolism Metastases Mice Mice, Inbred C57BL Oncology PD-1 protein PD-L1 protein Radiation (Physics) Retirement benefits Signal Transduction - physiology Skin T cells Transcription (Genetics) Transcription, Genetic - physiology Transcriptional Activation - physiology Transcriptional coactivators Tumors Ultraviolet radiation |
| title | Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy |
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