DOI QR코드

DOI QR Code

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)
  • 발행 : 2014.05.15

초록

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.

키워드

참고문헌

  1. 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. https://doi.org/10.7314/APJCP.2014.15.2.611
  2. 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. https://doi.org/10.3748/wjg.v19.i42.7374
  3. Diefenbach A, Raulet DH (1999). Natural killer cells: stress out, turn on, tune in. Curr Biol, 9, 851-3. https://doi.org/10.1016/S0960-9822(00)80044-5
  4. 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. https://doi.org/10.1007/s00432-012-1248-5
  5. 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. https://doi.org/10.1016/0092-8674(90)90591-2
  6. Gaffen SL, Liu KD (2004). Overview of interleukin-2 function, production and clinical applications. Cytokine, 28, 109-23. https://doi.org/10.1016/j.cyto.2004.06.010
  7. 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. https://doi.org/10.1038/nature03884
  8. Gasser S, Raulet DH (2006). Activation and self-tolerance of natural killer cells. Immunol Rev, 214, 130-42. https://doi.org/10.1111/j.1600-065X.2006.00460.x
  9. Holt GE, Podack ER, Raez LE (2011). Immunotherapy as a strategy for the treatment of non-small-cell lung cancer. Therapy, 8, 43-54. https://doi.org/10.2217/thy.10.84
  10. Karre K (2002). NK cells, MHC class I molecules and the missing self. Scand J Immunol, 55, 221-8. https://doi.org/10.1046/j.1365-3083.2002.01053.x
  11. 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. https://doi.org/10.1097/CJI.0b013e3181755deb
  12. 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. https://doi.org/10.1016/S0959-8049(96)00515-1
  13. Takiuchi H, Ajani JA (1998). Uracil-tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol, 16, 2877-85. https://doi.org/10.1200/JCO.1998.16.8.2877
  14. Macdonald JS, Astrow AB (2001). Adjuvant therapy of colon cancer. Semin Oncol, 28, 30-40. https://doi.org/10.1053/sonc.2001.20750
  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. https://doi.org/10.1146/annurev.immunol.19.1.197
  16. Ljunggren HG (2008). Cancer immunosurveillance: NKG2D breaks cover. Immunity, 28, 492-4. https://doi.org/10.1016/j.immuni.2008.03.007
  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. https://doi.org/10.1371/journal.ppat.1000798
  18. 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. https://doi.org/10.1371/journal.ppat.1000811
  19. Nausch N, Cerwenka A (2008). NKG2D ligands in tumor immunity. Oncogene, 27, 5944-58. https://doi.org/10.1038/onc.2008.272
  20. 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. https://doi.org/10.1016/j.molimm.2004.07.039
  21. 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. https://doi.org/10.1073/pnas.1219920110
  22. 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. https://doi.org/10.1016/S2213-2600(13)70009-2
  23. 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. https://doi.org/10.3748/wjg.v20.i4.1095
  24. Xu Y, Wang M (2014). Progress in immunotherapy for non-small cell lung Cancer. Zhongguo Fei Ai Za Zhi, 17, 34-41.
  25. 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. https://doi.org/10.1007/s00253-013-5349-0
  26. 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. https://doi.org/10.7314/APJCP.2014.15.1.265
  27. 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. https://doi.org/10.3109/07357907.2013.775294

피인용 문헌

  1. Overcoming 5-Fu Resistance of Colon Cells through Inhibition of Glut1 by the Specific Inhibitor WZB117 vol.15, pp.17, 2014, https://doi.org/10.7314/APJCP.2014.15.17.7037
  2. Interleukin-18 Synergism with Interleukin-2 in Cytotoxicity and NKG2D Expression of Human Natural Killer Cells vol.15, pp.18, 2014, https://doi.org/10.7314/APJCP.2014.15.18.7857
  3. The anti-cancerous activity of recombinant trichosanthin on prostate cancer cell PC3 vol.49, pp.1, 2016, https://doi.org/10.1186/s40659-016-0081-8
  4. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-09259-1