Browse > Article
http://dx.doi.org/10.7314/APJCP.2014.15.9.4039

5-Fluorouracil and Interleukin-2 Immunochemotherapy Enhances Immunogenicity of Non-Small Cell Lung Cancer A549 Cells through Upregulation of NKG2D Ligands  

Zhao, Lei (Institute of Frontier Medical Science, Jilin University)
Wang, Wen-Jia (Institute of Pharmaceutical Sciences, Jilin University)
Zhang, Jin-Nan (Department of Neurosurgery, Third Hospital, Jilin University)
Zhang, Xing-Yi (Second Hospital, Jilin University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.9, 2014 , pp. 4039-4044 More about this Journal
Abstract
Background: The aim of this study was to investigate the anti-cancer effects and mechanisms of immunochemotherapy of 5-fluorouracil (5-FU) and interleukin-2 (IL-2) on non-small cell lung cancer (NSCLC) A549 cells. Materials and Methods: In order to detect whether 5-FU+IL-2 could effectively inhibit tumor growth in vivo, we established an A549-bearing nude mouse model. The cytotoxicity of natural killer (NK) cells was evaluated using a standard chromium release assay. To evaluate the relevance of NK cells in 5-FU+IL-2-mediated tumor inhibitory effects, we depleted NK cells in A549-bearing mice by injecting anti-asialo-GM-1 antibodies. Effects of 5-FU+IL-2 on the expression and promoter activity of NKG2D ligands (MICA/MICB) in A549 cells in vitro were also assessed. Results: In A549-bearing nude mice, combination therapy significantly inhibited tumor growth in comparison with monotherapy with 5-FU or IL-2 and enhanced the recognition and lysis of tumor cells by NK cells. Further study of mechanisms showed that NK cells played a vital role in the anticancer immune response of 5-FU+IL-2 immunochemotherapy. In addition, the combination therapy synergistically stimulated the expression and promoter activity of MICA/MICB. Conclusions: 5-FU and IL-2 immunochemotherapy significantly inhibited tumor growth and activated NK cytotoxicity in vivo, and these effects were partly impaired after depleting NK cells in tumor-bearing mice. Combination treatment of 5-FU and IL-2 upregulated the expression and the promoter activity of MICA/MICB in A549 cells, which enhanced the recognition of A549 cells by NK cells. All of the data indicated that immunochemotherapy of 5-FU and IL-2 may provide a new treatment option for patients with lung cancer.
Keywords
5-FU; IL-2; immunochemotherapy; NK cell; MICA/B;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Wang ZX, Cao JX, Liu ZP, et al (2014). Combination of chemotherapy and immnotherapy for colon cancer in China: A meta-analysis. World J Gastroenterol, 20, 1095-106.   DOI   ScienceOn
2 Sandel MH, Speetjens FM, Menon AG, et al (2005). Natural killer cells infiltrating colorectal cancer and MHC class I expression. Mol Immunol, 42, 541-6.   DOI   ScienceOn
3 Siddle HV, Kreiss A, Tovar C, et al (2013). Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. Proc Natl Acad Sci USA, 110, 5103-8.   DOI   ScienceOn
4 Stella GM, Luisetti M, Pozzi E, et al (2013). Oncogenes in non-small-cell lung cancer: emerging connections and novel therapeutic dynamics. Lancet Respir Med, 1, 251-61.   DOI   ScienceOn
5 Xu Y, Wang M (2014). Progress in immunotherapy for non-small cell lung Cancer. Zhongguo Fei Ai Za Zhi, 17, 34-41.
6 Ye L, Fan J, Shi X, et al (2014). Tumor necrosis therapy antibody interleukin-2 fusion protein elicits prolonged and targeted antitumor effects in vivo. Appl Microbiol Biotechnol, 98, 4053-61.   DOI   ScienceOn
7 Yuan CH, Yang XQ, Zhu CL, et al (2014). Interleukin-7 enhances the in vivo anti-tumor activity of tumor-reactive CD8+ T cells with induction of IFN-gamma in a murine breast cancer model. Asian Pac J Cancer Prev, 15, 265-71.   과학기술학회마을   DOI   ScienceOn
8 Zheng YW, Li RM, Zhang XW, et al (2013). Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome. Cancer Invest, 31, 197-205.   DOI   ScienceOn
9 Savage P, Costelna D, Moore J, et al (1997). A phase II study of continuous infusional 5-fluorouracil and subcutaneous Interleukin-2 (IL-2) in metastatic renal cancer. Eur J Cancer, 33, 1149-51.   DOI   ScienceOn
10 Holt GE, Podack ER, Raez LE (2011). Immunotherapy as a strategy for the treatment of non-small-cell lung cancer. Therapy, 8, 43-54.   DOI   ScienceOn
11 Macdonald JS, Astrow AB (2001). Adjuvant therapy of colon cancer. Semin Oncol, 28, 30-40.   DOI
12 Karre K (2002). NK cells, MHC class I molecules and the missing self. Scand J Immunol, 55, 221-8.   DOI   ScienceOn
13 Kim JY, Bae JH, Lee SH, et al (2008). Induction of NKG2D ligands and subsequent enhancement of NK cell-mediated lysis of cancer cells by arsenic trioxide. J Immunother, 31, 475-86.   DOI
14 Takiuchi H, Ajani JA (1998). Uracil-tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol, 16, 2877-85.   DOI
15 Moretta A, Bottino C, Vitale M, et al (2001). Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol, 19, 197-223.   DOI   ScienceOn
16 Ljunggren HG (2008). Cancer immunosurveillance: NKG2D breaks cover. Immunity, 28, 492-4.   DOI   ScienceOn
17 Makedonas G, Hutnick N, Haney D, et al (2010). Perforin and IL-2 upregulation define qualitative differences among highly functional virus-specific human CD8 T cells. PLoS Pathog, 6, 1000798.   DOI   ScienceOn
18 Nausch N, Cerwenka A (2008). NKG2D ligands in tumor immunity. Oncogene, 27, 5944-58.   DOI   ScienceOn
19 Ahmed Ali HA, Di J, Mei W, et al (2014). Antitumor activity of lentivirus-mediated interleukin -12 gene modified dendritic cells in human lung cancer in vitro. Asian Pac J Cancer Prev, 15, 611-6.   과학기술학회마을   DOI   ScienceOn
20 Diefenbach A, Raulet DH (1999). Natural killer cells: stress out, turn on, tune in. Curr Biol, 9, 851-3.   DOI   ScienceOn
21 Gasser S, Orsulic S, Brown EJ, et al (2005). The DNA damage pathway regulates innatemimune system ligands for the NKG2D receptor. Nature, 436, 1186-90.   DOI   ScienceOn
22 Du G, Ye L, Zhang G, et al (2012). Human IL18-IL2 fusion protein as a potential antitumor reagent by enhancing NK cell cytotoxicity and IFN-$\gamma$ production. J Cancer Res Clin Oncol, 138, 1727-36.   DOI   ScienceOn
23 Fearon ER, Pardoll DM, Itaya T, et al (1990). Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell, 60, 397-403.   DOI   ScienceOn
24 Gaffen SL, Liu KD (2004). Overview of interleukin-2 function, production and clinical applications. Cytokine, 28, 109-23.   DOI   ScienceOn
25 Gasser S, Raulet DH (2006). Activation and self-tolerance of natural killer cells. Immunol Rev, 214, 130-42.   DOI   ScienceOn
26 Martinez J, Huang X, Yang Y (2010). Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection. PLoS Pathog, 6, 1000811.   DOI   ScienceOn
27 Das D, Preet R, Mohapatra P, et al (2013). 1, 3-Bis (2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/resistant colon cancer cells. World J Gastroenterol, 19, 7374-88.   DOI   ScienceOn