4-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor
4-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor
Hui QIU1, Hui ZHANG2, Zuohua FENG2()
1. Department of Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China; 2. Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
The interaction by co-stimulatory molecules 4-1BB and 4-1BB ligand (4-1BBL) plays an important role in the activation, proliferation and differentiation of T lymphocytes. The function of 4-1BB/4-1BBL expressed by the immune cells has been the focus for many tumor immunotherapy efforts. In this study, 4-1BBL was expressed in non-immune cells and non-tumor cells, and the role of 4-1BBL in lymphocyte activation and tumor suppression was investigated. The plasmid p4-1BBL containing the full length of mouse 4-1BBL cDNA sequence was constructed, and the plasmid was transfected into baby hamster kidney (BHK) cells and murine muscle cells by means of lipofectin-mediated or naked plasmid DNA injection into the muscle directly. The study demonstrated that the molecule 4-1BBL expressed by BHK cells in vitro could enhance the proliferation and cytotoxicity of lymphocytes, and it could increase the expression level of IL-2 and IFN-γ. The treatment with plasmid p4-1BBL in vivo revealed that the number of CD8+ T cells in the peri-tumoral tissue increased markedly, and the growth rate of the tumor was significantly lower than that of control group. These findings suggest that expression of 4-1BBL by normal cells in the tumor microenvironment can enhance the proliferation and other functions of T lymphocytes. This therapeutic method may provide a promising approach for tumor immunotherapy.
. 4-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor[J]. Frontiers of Medicine in China, 2009, 3(1): 20-25.
Hui QIU, Hui ZHANG, Zuohua FENG. 4-1BBL expressed by eukaryotic cells activates immune cells and suppresses the progression of murine tumor. Front Med Chin, 2009, 3(1): 20-25.
Goodwin R G, Din W S, Davis-Smith T, Anderson D M, Gimpel S D, Sato T A, Maliszewski C R, Brannan C I, Copeland N G, Jenkins N A. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur J Immuno , 1993, 23(10): 2631-2641 doi: 10.1002/eji.1830231037
2
Pollok K E, Kim Y J, Zhou Z, Hurtado J, Kim K K, Pickard R T, Kwon B S. Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol , 1993, 150(3): 771-781
3
Wilcox R A, Chapoval A I, Gorski K S, Otsuji M, Shin T, Flies D B, Tamada K, Mittler R S, Tsuchiya H, Pardoll D M, Chen L. Cutting edge: expression of functional CD137 receptor by dendritic cells. J Immunol , 2002, 168(9): 4262-4267
4
DeBenedette M A, Shahinian A, Mak T W, Watts T H. Costimulation of CD28-T lymphocytes by 4-1BB ligand. J Immunol , 1997, 158(2): 551-559
5
Cannons J L, Lau P, Ghumman B, DeBenedette M A, Yagita H, Okumura K, Watts T H. 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J Immunol , 2001, 167(3): 1313-1324
6
Shuford W W, Klussman K, Tritchler D D, Loo D T, Chalupny J, Siadak A W, Brown T J, Emswiler J, Raecho H, Larsen C P, Pearson T C, Ledbetter J A, Aruffo A, Mittler R S. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med , 1997, 186(1): 47-55 doi: 10.1084/jem.186.1.47
7
Saoulli K, Lee S Y, Cannons J L, Yeh W C, Santana A, Goldstein M D, Bangia N, DeBenedette M A, Mak T W, Choi Y, Watts T H. CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J Exp Med , 1998, 187(11): 849-862 doi: 10.1084/jem.187.11.1849
8
Strome S E, Martin B, Flies D, Tamada K, Chapoval A I, Sargent DJ, Shu S, Chen L. Enhanced therapeutic potential of adoptive immunotherapy by in vitro CD28/4-1BB costimulation of tumor-reactive T cells against a poorly immunogenic, major histocompatibility complex class I-negative A9P melanoma. J Immunother , 2000, 23(4): 430-437 doi: 10.1097/00002371-200007000-00006
9
Xiang J. Expression of co-stimulatory 4-1BB ligand induces significant tumor regression and protective immunity. Cancer Biother Radiopharm , 1999, 14(5): 353-361 doi: 10.1089/cbr.1999.14.353
10
O'Driscoll L, Daly C, Saleh M, Clynes M. The use of reverse transcriptase-polymerase chain reaction (RT-PCR) to investigate specific gene expression in multidrug-resistant cells. Cytotechnology , 1993, 12(1-3): 289-314 doi: 10.1007/BF00744669
11
Lee N, Zhang S Q, Testa D. A rapid multicolor Western blot. J Immunol Methods , 1988, 106(1): 27-30 doi: 10.1016/0022-1759(88)90267-0
12
Schmidt-Kastner R, Meller D, Bellander B M, Str?mberg I, Olson L, Ingvar M. A one-step immunohistochemical method for detection of blood-brain barrier disturbances for immunoglobulins in lesioned rat brain with special reference to false-positive labeling in immunohistochemistry. J Neurosci Methods , 1993, 46(2): 121-132 doi: 10.1016/0165-0270(93)90147-J
13
Feng Z, Huang B, Zhang G, Li D, Wang H. Investigation on the effect of peptides mixture from tumor cells inducing anti-tumor specific immune response. Sci China C Life Sci , 2002, 45(4): 361-369 doi: 10.1360/02yc9040
14
Blachere N E, Li Z, Chandawarkar R Y, Suto R, Jaikaria N S, Basu S, Udono H, Srivastava P K. Heat shock protein-peptide complexes reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med , 1997, 186(8): 1315-1322 doi: 10.1084/jem.186.8.1315
15
Huang B, Feng Z, Zhang G, Li D, Wang H. Hsp70-H22 tumor antigen peptide complex activated dendritic cell in the induction of antitumor immunity. Zhonghua Zhong Liu Za Zhi , 2002, 24(5): 421-425 (in Chinese)
16
Ferrari M, Fornasiero M C, Isetta A M. MTT colorimetric assay for testing macrophage cytotoxic activity in vitro. J Immunol Methods , 1990, 131(2): 165-172 doi: 10.1016/0022-1759(90)90187-Z
17
Feng Z, Zhang G, Huang B, Li D, Wang H. Inducement of specific CTLs by antigen-peptides from human leukemia cells and their cytotoxicity to leukemia cells. J Huazhong Univ Sci Technol Med Sci , 2002, 22(4): 265-269
18
Kubota A, Lian R H, Lohwasser S, Salcedo M, Takei F. IFN-gamma production and cytotoxicity of IL-2-activated murine NK cells are differentially regulated by MHC class I molecules. J Immunol , 1999, 163(12): 6488-6493
19
Puliaev R, Nguyen P, Finkelman F D, Via C S. Differential requirement for IFN-gamma in CTL maturation in acute murine graft-versus-host disease. J Immunol , 2004, 173(2): 910-919
20
Langstein J, Becke F M, S?llner L, Krause G, Brockhoff G, Kreutz M, Andreesen R, Schwarz H. Comparative analysis of CD137 and LPS effects on monocyte activation, survival, and proliferation. Biochem Biophys Res Commun , 2000, 273(1): 117-122 doi: 10.1006/bbrc.2000.2889
21
Nam K O, Shin S M, Lee H W. Cross-linking of 4-1BB up-regulates IL-13 expression in CD8(+) T lymphocytes. Cytokine , 2006, 33(2): 87-94 doi: 10.1016/j.cyto.2005.12.003
22
Ju S A, Lee S C, Kwon T H, Heo S K, Park S M, Paek H N, Suh J H, Cho H R, Kwon B, Kwon B S, Kim B S. Immunity to melanoma mediated by 4-1BB is associated with enhanced activity of tumour-infiltrating lymphocytes. Immunol Cell Biol , 2005, 83(4): 344-351 doi: 10.1111/j.1440-1711.2005.01330.x
23
Lee H W, Park S J, Choi B K, Kim H H, Nam K O, Kwon B S. 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J Immunol 2002, 169(9): 4882-4888