HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by He, Y.-F. Articles by Feng, Z.-H. Search for Related Content PubMed PubMed Citation Articles by He, Y.-F. Articles by Feng, Z.-H.

Blocking Programmed Death-1 Ligand-PD-1 Interactions by Local Gene Therapy Results in Enhancement of Antitumor Effect of Secondary Lymphoid Tissue Chemokine¹

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The People’s Republic of China

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 µg but not 100 or 200 µg. 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.

This article has been cited by other articles:

				C. Lin, W. Wei, J. Zhang, S. Liu, Y. Liu, and D. Zheng Formyl peptide receptor-like 1 mediated endogenous TRAIL gene expression with tumoricidal activity Mol. Cancer Ther., October 1, 2007; 6(10): 2618 - 2625. [Abstract] [Full Text] [PDF]

				T. Okazaki and T. Honjo PD-1 and PD-1 ligands: from discovery to clinical application Int. Immunol., July 2, 2007; (2007) dxm057v1. [Abstract] [Full Text] [PDF]

				J. Liu, A. Hamrouni, D. Wolowiec, V. Coiteux, K. Kuliczkowski, D. Hetuin, A. Saudemont, and B. Quesnel Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway Blood, July 1, 2007; 110(1): 296 - 304. [Abstract] [Full Text] [PDF]

				H. Xiao, B. Huang, Y. Yuan, D. Li, L.-F. Han, Y. Liu, W. Gong, F.-H. Wu, G.-M. Zhang, and Z.-H. Feng Soluble PD-1 Facilitates 4-1BBL-Triggered Antitumor Immunity against Murine H22 Hepatocarcinoma In vivo Clin. Cancer Res., March 15, 2007; 13(6): 1823 - 1830. [Abstract] [Full Text] [PDF]

				H. Geng, G.-M. Zhang, D. Li, H. Zhang, Y. Yuan, H.-G. Zhu, H. Xiao, L.-F. Han, and Z.-H. Feng Soluble Form of T Cell Ig Mucin 3 Is an Inhibitory Molecule in T Cell-Mediated Immune Response J. Immunol., February 1, 2006; 176(3): 1411 - 1420. [Abstract] [Full Text] [PDF]