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Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine
The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, costimulatory molecules PD-L1 (also B7-H1) and PD-L2 (also B7-DC), is involved in the mechanisms of tumor immune evasion. In this study, we found that this negative signal was also involved in immune evasion i...
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Published in: | The Journal of immunology (1950) 2004-10, Vol.173 (8), p.4919-4928 |
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container_title | The Journal of immunology (1950) |
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creator | He, Yu-Fei Zhang, Gui-Mei Wang, Xiao-Hong Zhang, Hui Yuan, Ye Li, Dong Feng, Zuo-Hua |
description | The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, costimulatory molecules PD-L1 (also B7-H1) and PD-L2 (also B7-DC), is involved in the mechanisms of tumor immune evasion. In this study, we found that this negative signal was also involved in immune evasion in tumor immunotherapy. When we used different doses of a constructed eukaryotic expression plasmid, pSLC, which expresses functional murine secondary lymphoid tissue chemokine (SLC, CCL21), to treat BALB/c mice inoculated with H22 murine hepatoma cells, the inhibitory effect was enhanced along with the increase of pSLC dosage. Unexpectedly, however, the best complete inhibition rate of tumor was reached when pSLC was used at the dosage of 50 microg but not 100 or 200 microg. RT-PCR and real-time PCR revealed that both PD-L1 and PD-L2 genes were expressed in tumor and vicinal muscle tissues of tumor-bearing mice and the expression level was significantly increased if a higher dosage of pSLC was administered. We then constructed a eukaryotic expression plasmid (pPD-1A) that expresses the extracellular domain of murine PD-1 (sPD-1). sPD-1 could bind PD-1 ligands, block PD-Ls-PD-1 interactions, and enhance the cytotoxicity of tumor-specific CTL. Local gene transfer by injection of pPD-1A mediated antitumor effect and improved SLC-mediated antitumor immunity. The combined gene therapy with SLC plus sPD-1 did not induce remarkable autoimmune manifestations. Our findings provide a potent method of improving the antitumor effects of SLC and possibly other immunotherapeutic methods by local blockade of negative costimulatory molecules. |
doi_str_mv | 10.4049/jimmunol.173.8.4919 |
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In this study, we found that this negative signal was also involved in immune evasion in tumor immunotherapy. When we used different doses of a constructed eukaryotic expression plasmid, pSLC, which expresses functional murine secondary lymphoid tissue chemokine (SLC, CCL21), to treat BALB/c mice inoculated with H22 murine hepatoma cells, the inhibitory effect was enhanced along with the increase of pSLC dosage. Unexpectedly, however, the best complete inhibition rate of tumor was reached when pSLC was used at the dosage of 50 microg but not 100 or 200 microg. RT-PCR and real-time PCR revealed that both PD-L1 and PD-L2 genes were expressed in tumor and vicinal muscle tissues of tumor-bearing mice and the expression level was significantly increased if a higher dosage of pSLC was administered. We then constructed a eukaryotic expression plasmid (pPD-1A) that expresses the extracellular domain of murine PD-1 (sPD-1). sPD-1 could bind PD-1 ligands, block PD-Ls-PD-1 interactions, and enhance the cytotoxicity of tumor-specific CTL. Local gene transfer by injection of pPD-1A mediated antitumor effect and improved SLC-mediated antitumor immunity. The combined gene therapy with SLC plus sPD-1 did not induce remarkable autoimmune manifestations. Our findings provide a potent method of improving the antitumor effects of SLC and possibly other immunotherapeutic methods by local blockade of negative costimulatory molecules.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.173.8.4919</identifier><identifier>PMID: 15470033</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Animals ; Antigens, Surface - genetics ; Antigens, Surface - metabolism ; Apoptosis Regulatory Proteins ; B7-1 Antigen - genetics ; B7-1 Antigen - metabolism ; B7-H1 Antigen ; Blood Proteins - genetics ; Blood Proteins - metabolism ; Cell Line ; Chemokine CCL21 ; Chemokines, CC - genetics ; Female ; Genetic Therapy ; HSP70 Heat-Shock Proteins - pharmacology ; Liver Neoplasms, Experimental - therapy ; Membrane Glycoproteins ; Mice ; Mice, Inbred BALB C ; Peptides - genetics ; Peptides - metabolism ; Programmed Cell Death 1 Ligand 2 Protein ; Programmed Cell Death 1 Receptor ; Transfection</subject><ispartof>The Journal of immunology (1950), 2004-10, Vol.173 (8), p.4919-4928</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-730b13bf0381331ca266552ee7753365819e011be183451841486df131ae42fe3</citedby><cites>FETCH-LOGICAL-c475t-730b13bf0381331ca266552ee7753365819e011be183451841486df131ae42fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15470033$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>He, Yu-Fei</creatorcontrib><creatorcontrib>Zhang, Gui-Mei</creatorcontrib><creatorcontrib>Wang, Xiao-Hong</creatorcontrib><creatorcontrib>Zhang, Hui</creatorcontrib><creatorcontrib>Yuan, Ye</creatorcontrib><creatorcontrib>Li, Dong</creatorcontrib><creatorcontrib>Feng, Zuo-Hua</creatorcontrib><title>Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, costimulatory molecules PD-L1 (also B7-H1) and PD-L2 (also B7-DC), is involved in the mechanisms of tumor immune evasion. 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We then constructed a eukaryotic expression plasmid (pPD-1A) that expresses the extracellular domain of murine PD-1 (sPD-1). sPD-1 could bind PD-1 ligands, block PD-Ls-PD-1 interactions, and enhance the cytotoxicity of tumor-specific CTL. Local gene transfer by injection of pPD-1A mediated antitumor effect and improved SLC-mediated antitumor immunity. The combined gene therapy with SLC plus sPD-1 did not induce remarkable autoimmune manifestations. Our findings provide a potent method of improving the antitumor effects of SLC and possibly other immunotherapeutic methods by local blockade of negative costimulatory molecules.</description><subject>Animals</subject><subject>Antigens, Surface - genetics</subject><subject>Antigens, Surface - metabolism</subject><subject>Apoptosis Regulatory Proteins</subject><subject>B7-1 Antigen - genetics</subject><subject>B7-1 Antigen - metabolism</subject><subject>B7-H1 Antigen</subject><subject>Blood Proteins - genetics</subject><subject>Blood Proteins - metabolism</subject><subject>Cell Line</subject><subject>Chemokine CCL21</subject><subject>Chemokines, CC - genetics</subject><subject>Female</subject><subject>Genetic Therapy</subject><subject>HSP70 Heat-Shock Proteins - pharmacology</subject><subject>Liver Neoplasms, Experimental - therapy</subject><subject>Membrane Glycoproteins</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Peptides - genetics</subject><subject>Peptides - metabolism</subject><subject>Programmed Cell Death 1 Ligand 2 Protein</subject><subject>Programmed Cell Death 1 Receptor</subject><subject>Transfection</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqFkdFu0zAUQC0EYmXwBUjIT_CU4hs7TvI4urJNqsQE5dlykpvGI7aLnajqv_CxeGsRvPFkyz73yNYh5C2wpWCi_vhgrJ2dH5dQ8mW1FDXUz8gCioJlUjL5nCwYy_MMSllekFcxPjDGJMvFS3IBhSgZ43xBfn0affvDuB29D34XtLXY0WvU05AB3Ziddl12f532d27CoNvJeBdpc6Qb3-qR3qBDuh3Szf5Iv2KcxylS4-jaDdq1aNFN1Pf0yk1mmq0PdN332D6dfcPWu06HpDra_eBNR7cmxhnpakDr05vwNXnR6zHim_N6Sb5_Xm9Xt9nmy83d6mqTtaIspqzkrAHe9IxXwDm0OpeyKHLEsiw4l0UFNTKABqHiooBKgKhk1wMHjSLvkV-S9yfvPvifM8ZJWRNbHEft0M9RSVkXkNfwXxAqxsvkTyA_gW3wMQbs1T4Ymz6rgKnHeupPPZXqqUo91ktT7876uUkd_s6ccyXgwwkYzG44mIAqWj2OCQd1OBz-Uf0GQWClkw</recordid><startdate>20041015</startdate><enddate>20041015</enddate><creator>He, Yu-Fei</creator><creator>Zhang, Gui-Mei</creator><creator>Wang, Xiao-Hong</creator><creator>Zhang, Hui</creator><creator>Yuan, Ye</creator><creator>Li, Dong</creator><creator>Feng, Zuo-Hua</creator><general>Am Assoc Immnol</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>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20041015</creationdate><title>Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine</title><author>He, Yu-Fei ; Zhang, Gui-Mei ; Wang, Xiao-Hong ; Zhang, Hui ; Yuan, Ye ; Li, Dong ; Feng, Zuo-Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-730b13bf0381331ca266552ee7753365819e011be183451841486df131ae42fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antigens, Surface - genetics</topic><topic>Antigens, Surface - metabolism</topic><topic>Apoptosis Regulatory Proteins</topic><topic>B7-1 Antigen - genetics</topic><topic>B7-1 Antigen - metabolism</topic><topic>B7-H1 Antigen</topic><topic>Blood Proteins - genetics</topic><topic>Blood Proteins - metabolism</topic><topic>Cell Line</topic><topic>Chemokine CCL21</topic><topic>Chemokines, CC - genetics</topic><topic>Female</topic><topic>Genetic Therapy</topic><topic>HSP70 Heat-Shock Proteins - pharmacology</topic><topic>Liver Neoplasms, Experimental - therapy</topic><topic>Membrane Glycoproteins</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Peptides - genetics</topic><topic>Peptides - metabolism</topic><topic>Programmed Cell Death 1 Ligand 2 Protein</topic><topic>Programmed Cell Death 1 Receptor</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>He, Yu-Fei</creatorcontrib><creatorcontrib>Zhang, Gui-Mei</creatorcontrib><creatorcontrib>Wang, Xiao-Hong</creatorcontrib><creatorcontrib>Zhang, Hui</creatorcontrib><creatorcontrib>Yuan, Ye</creatorcontrib><creatorcontrib>Li, Dong</creatorcontrib><creatorcontrib>Feng, Zuo-Hua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>He, Yu-Fei</au><au>Zhang, Gui-Mei</au><au>Wang, Xiao-Hong</au><au>Zhang, Hui</au><au>Yuan, Ye</au><au>Li, Dong</au><au>Feng, Zuo-Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2004-10-15</date><risdate>2004</risdate><volume>173</volume><issue>8</issue><spage>4919</spage><epage>4928</epage><pages>4919-4928</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, costimulatory molecules PD-L1 (also B7-H1) and PD-L2 (also B7-DC), is involved in the mechanisms of tumor immune evasion. 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We then constructed a eukaryotic expression plasmid (pPD-1A) that expresses the extracellular domain of murine PD-1 (sPD-1). sPD-1 could bind PD-1 ligands, block PD-Ls-PD-1 interactions, and enhance the cytotoxicity of tumor-specific CTL. Local gene transfer by injection of pPD-1A mediated antitumor effect and improved SLC-mediated antitumor immunity. The combined gene therapy with SLC plus sPD-1 did not induce remarkable autoimmune manifestations. Our findings provide a potent method of improving the antitumor effects of SLC and possibly other immunotherapeutic methods by local blockade of negative costimulatory molecules.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>15470033</pmid><doi>10.4049/jimmunol.173.8.4919</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antigens, Surface - genetics Antigens, Surface - metabolism Apoptosis Regulatory Proteins B7-1 Antigen - genetics B7-1 Antigen - metabolism B7-H1 Antigen Blood Proteins - genetics Blood Proteins - metabolism Cell Line Chemokine CCL21 Chemokines, CC - genetics Female Genetic Therapy HSP70 Heat-Shock Proteins - pharmacology Liver Neoplasms, Experimental - therapy Membrane Glycoproteins Mice Mice, Inbred BALB C Peptides - genetics Peptides - metabolism Programmed Cell Death 1 Ligand 2 Protein Programmed Cell Death 1 Receptor Transfection |
title | Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine |
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