Anticancer Effect of Activated Natural Killer Cells on Human Colorectal Tumor

결장암에 대한 활성 자연살해세포의 항암효능

  • Sung, Hye-Ran (Department of Comprehensive Melanoma Research Center (CMRC), H. Lee Moffitt Cancer Center & Research Institute) ;
  • Kim, Jee-Youn (College of Pharmacy, Chungbuk National University) ;
  • Park, Min-Gyeong (College of Pharmacy, Chungbuk National University) ;
  • Kim, Il-Hoi (College of Pharmacy, Chungbuk National University) ;
  • Lee, Dong-Wook (College of Pharmacy, Chungbuk National University) ;
  • Han, Sang-Bae (College of Pharmacy, Chungbuk National University) ;
  • Lee, Chong-Kil (College of Pharmacy, Chungbuk National University) ;
  • Song, Suk-Gil (College of Pharmacy, Chungbuk National University)
  • Received : 2010.05.10
  • Accepted : 2010.05.18
  • Published : 2010.06.30

Abstract

Colorectal cancer is one of the most common alimentary malignancies. In this study, the antitumor activity of activated human natural killer (NK) cells against human colorectal cancer was evaluated in vivo. Human NK cells are the key contributors of innate immune response and the effective functions of these cells are enhanced by cytokines. Human peripheral blood mononuclear cells (PBMC) were cultured with interleukin-2 (IL-2)-containing medium for 14 days and resulted in enriched NK cell population. The resulting populations of the cells comprised 7% $CD3^+CD4^+$ cells, 25% $CD3^+CD8^+$ cells, 13% $CD3^-CD8^+$ cells, 4% $CD3^+$CD16/$CD56^+$ cells, 39% $CD3^+$CD16/$CD56^-$ cells, and 52% $CD3^-$CD16/$CD56^+$ cells. Tumor necrosis factor alpha (TNF-$\alpha$), interferon gamma (IFN-$\gamma$), IL-2, IL-4, and IL-5 transcripts of the activated NK cells were confirmed by RT-PCR. In addition, activated NK cells at doses of 2.5, 5 and 10 million cells per mouse inhibited 10%, 34% and 47% of SW620-induced tumor growth in nude mouse xenograft assays, respectively. This study suggests that NK cell-based immunotherapy may be used as an adoptive immunotherapy for colorectal cancer patients.

Keywords

References

  1. Davis, D. L., Hoel, D., Fox, J. and Lopez, A. : International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA. Lancet 336, 474 (1990). https://doi.org/10.1016/0140-6736(90)92020-I
  2. Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T. and Thun, M. J. : Cancer statistics, 2008. CA Cancer. J. Clin. 58, 71 (2008).
  3. Bar-Sela, G. and Haim, N. : Abnoba-viscum (mistletoe extract) in metastatic colorectal carcinoma resistant to 5-fluorouracil and leucovorin-based chemotherapy. Med. Oncol. 21, 251 (2004). https://doi.org/10.1385/MO:21:3:251
  4. de Gramont, A., Tournigand, C., Louvet, C., Maindrault-Goebel, F. and Andre, T. : First-line therapy for advanced colorectal cancer. Curr. Oncol. Rep. 7, 167 (2005). https://doi.org/10.1007/s11912-005-0069-y
  5. Joosten, J., Jager, G., Oyen, W., Wobbes, T. and Ruers, T. : Cryosurgery and radiofrequency ablation for unresectable colorectal liver metastases. Eur. J. Surg. Oncol. 31, 1152 (2005). https://doi.org/10.1016/j.ejso.2005.07.010
  6. Gravalos, C., García-Sanchez, L., Hernandez, M., Holgado, E., Alvarez, N., García-Escobar, I., Martínez, J. and Robles, L. : Surgical resection of a solitary pancreatic metastasis from colorectal cancer: a new step to a cure? Clin. Colorectal. Cancer. 7, 398 (2008). https://doi.org/10.3816/CCC.2008.n.053
  7. Renouf, D., Kennecke, H. and Gill, S. : Trends in chemotherapy utilization for colorectal cancer. Clin. Colorectal. Cancer. 7, 386 (2008). https://doi.org/10.3816/CCC.2008.n.051
  8. Kiessling, R., Klein, E. and Wigzell, H. : "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 5, 112 (1975). https://doi.org/10.1002/eji.1830050208
  9. Lanier, L. L. : NK cell recognition. Annu. Rev. Immunol. 23, 225 (2005). https://doi.org/10.1146/annurev.immunol.23.021704.115526
  10. Bryceson, Y. T., March, M. E., Ljunggren, H. G. and Long, E. O. : Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 214, 73 (2006). https://doi.org/10.1111/j.1600-065X.2006.00457.x
  11. Ljunggren, H. G. and Malmberg, K. J. : Prospects for the use of NK cells in immunotherapy of human cancer. Nat. Rev. Immunol. 7, 329 (2007). https://doi.org/10.1038/nri2073
  12. Han, S. B., Lee, C. W., Jeon, Y. J., Hong, N. D., Yoo, I. D., Yang, K. H. and Kim, H. M. : The inhibitory effect of polysaccharides isolated from Phellinus linteus on tumor growth and metastasis. Immunopharmacology 41, 157 (1999). https://doi.org/10.1016/S0162-3109(98)00063-0
  13. Han, S. B., Moratz, C., Huang, N. N., Kelsall, B., Cho, H., Shi, C. S., Schwartz, O. and Kehrl, J. H. : Rgs1 and Gnai2 regulate the entrance of B lymphocytes into lymph nodes and B cell motility within lymph node follicles. Immunity 22, 343 (2005). https://doi.org/10.1016/j.immuni.2005.01.017
  14. Greenlee, R. T., Murray, T., Bolden, S. and Wingo, P. A. : Cancer statistics, 2000. CA Cancer. J. Clin. 50, 7 (2000).
  15. Moore, H. C. and Haller, D. G. : Adjuvant therapy of colon cancer. Semin Oncol. 26, 545 (1999).
  16. Chung, K. Y. and Saltz, L. B. : Antibody-based therapies for colorectal cancer. Oncologist. 10, 701 (2005). https://doi.org/10.1634/theoncologist.10-9-701
  17. Kelly, H. and Goldberg, R. M. : Systemic therapy for metastatic colorectal cancer: current options, current evidence. J. Clin. Oncol. 23, 4553 (2005). https://doi.org/10.1200/JCO.2005.17.749
  18. Pozzo, C., Barone, C., Szanto, J., Padi, E., Peschel, C., Bukki, J., Gorbunova, V., Valvere, V., Zaluski, J., Biakhov, M., Zuber, E., Jacques, C. and Bugat, R. : Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Ann. Oncol. 15, 1773 (2004). https://doi.org/10.1093/annonc/mdh473
  19. Todryk, S. M., Chong, H., Vile, R. G., Pandha, H. and Lemoine, N. R. : Can immunotherapy by gene transfer tip the balance against colorectal cancer? Gut. 43, 445 (1998). https://doi.org/10.1136/gut.43.4.445
  20. Yip, D., Strickland, A. H., Karapetis, C. S., Hawkins, C. A. and Harper, P. G. : Immunomodulation therapy in colorectal carcinoma. Cancer. Treat. Rev. 26, 169 (2000). https://doi.org/10.1053/ctrv.1999.0160
  21. Mann, B., Gratchev, A., Böhm, C., Hanski, M. L., Foss, H. D., Demel, G., Trojanek, B., Schmidt-Wolf, I., Stein, H., Riecken, E. O., Buhr, H. J. and Hanski, C. : FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas. Br. J. Cancer. 79, 1262 (1999). https://doi.org/10.1038/sj.bjc.6690202
  22. Nakagomi, H., Petersson, M., Magnusson, I., Juhlin, C., Matsuda, M., Mellstedt, H., Taupin, J. L., Vivier, E., Anderson, P. and Kiessling, R. : Decreased expression of the signaltransducing zeta chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer. Res. 53, 5610 (1993).
  23. Bremers, A. J., Kuppen, P. J. and Parmiani, G. : Tumour immunotherapy: the adjuvant treatment of the 21st century? Eur. J. Surg. Oncol. 26, 418 (2000). https://doi.org/10.1053/ejso.1999.0908
  24. Kalinski, P., Nakamura, Y., Watchmaker, P., Giermasz, A., Muthuswamy, R. and Mailliard, R. B. : Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Polarized dendritic cells as cancer vaccines. Immunol. Res. 36, 137 (2006). https://doi.org/10.1385/IR:36:1:137
  25. Raja, Gabaglia, C., Diaz, de Durana, Y., Graham, F. L., Gauldie, J., Sercarz, E. E. and Braciak, T. A. : Attenuation of the glucocorticoid response during Ad5IL-12 adenovirus vector treatment enhances natural killer cell-mediated killing of MHC class I-negative LNCaP prostate tumors. Cancer Res. 67, 2290 (2007). https://doi.org/10.1158/0008-5472.CAN-06-3399
  26. Takashima, K., Fujiwara, H., Inada, S., Atsuji, K., Araki, Y., Kubota, T. and Yamagishi, H. : Tracking of green fluorescent protein (GFP)-labeled LAK cells in mice carrying B16 melanoma metastases. Anticancer Res. 26, 3327 (2006).
  27. Thorne, S. H., Negrin, R. S. and Contag, C. H. : Synergistic antitumor effects of immune cell-viral biotherapy. Science 311, 1780 (2006). https://doi.org/10.1126/science.1121411
  28. Wang, W., Epler, J., Salazar, L. G. and Riddell, S. R. : Recognition of breast cancer cells by CD8+ cytotoxic T-cell clones specific for NY-BR-1. Cancer. Res. 66, 6826 (2006). https://doi.org/10.1158/0008-5472.CAN-05-3529
  29. Kim, H. M., Kang, J. S., Lim, J., Park, S. K., Lee, K., Yoon, Y. D., Lee, C. W., Lee, K. H., Han, G., Yang, K. H., Kim, Y. J., Kim, Y. and Han, S. B. : Inhibition of human ovarian tumor growth by cytokine-induced killer cells. Arch. Pharm. Res. 30, 1464 (2007). https://doi.org/10.1007/BF02977372
  30. Grabert, R. C., Cousens, L. P., Smith, J. A., Olson, S., Gall, J., Young, W. B., Davol, P. A. and Lum, L. G. : Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation. Clin. Cancer. Res. 12, 569 (2006). https://doi.org/10.1158/1078-0432.CCR-05-2005
  31. Burns, L. J., Weisdorf, D. J., DeFor, T. E., Vesole, D. H., Repka, T. L., Blazar, B. R., Burger, S. R., Panoskaltsis-Mortari, A., Keever-Taylor, C. A., Zhang, M. J. and Miller, J. S. : IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone. Marrow. Transplant. 32, 177 (2003). https://doi.org/10.1038/sj.bmt.1704086
  32. Imai, K., Matsuyama, S., Miyake, S., Suga, K. and Nakachi, K. : Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 356, 1795 (2000). https://doi.org/10.1016/S0140-6736(00)03231-1
  33. Bobek, V., Boubelik, M., Fiserova, A., L'uptovcova, M., Vannucci, L., Kacprzak, G., Kolodzej, J., Majewski, A. M. and Hoffman, R. M. : Anticoagulant drugs increase natural killer cell activity in lung cancer. Lung. Cancer. 47, 215 (2005). https://doi.org/10.1016/j.lungcan.2004.06.012
  34. Whiteside, T. L. and Herberman, R. B. : Role of human natural killer cells in health and disease. Clin. Diagn. Lab. Immunol. 1, 125 (1994).
  35. Ishigami, S., Natsugoe, S., Tokuda, K., Nakajo, A., Che, X., Iwashige, H., Aridome, K., Hokita, S. and Aikou, T. : Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 88, 577 (2000). https://doi.org/10.1002/(SICI)1097-0142(20000201)88:3<577::AID-CNCR13>3.0.CO;2-V
  36. Takanami, I., Takeuchi, K. and Giga, M. : The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma. J. Thorac. Cardiovasc. Surg. 121, 1058 (2001). https://doi.org/10.1067/mtc.2001.113026
  37. Coca, S., Perez-Piqueras, J., Martinez, D., Colmenarejo, A., Saez, M. A., Vallejo, C., Martos, J. A. and Moreno, M. : The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer. 79, 2320 (1997). https://doi.org/10.1002/(SICI)1097-0142(19970615)79:12<2320::AID-CNCR5>3.0.CO;2-P
  38. Dewan, M. Z., Terunuma, H., Toi, M., Tanaka, Y., Katano, H., Deng, X., Abe, H., Nakasone, T., Mori, N., Sata, T. and Yamamoto, N. : Potential role of natural killer cells in controlling growth and infiltration of AIDS-associated primary effusion lymphoma cells. Cancer. Sci. 97, 1381 (2006). https://doi.org/10.1111/j.1349-7006.2006.00319.x
  39. Dewan, M. Z., Terunuma, H., Takada, M., Tanaka, Y., Abe, H., Sata, T., Toi, M. and Yamamoto, N. : Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo. Breast Cancer. Res. Treat. 104, 267 (2007). https://doi.org/10.1007/s10549-006-9416-4
  40. Escudier, B., Farace, F., Angevin, E., Charpentier, F., Nitenberg, G., Triebel, F. and Hercend, T. : Immunotherapy with interleukin-2 (IL2) and lymphokine-activated natural killer cells: improvement of clinical responses in metastatic renal cell carcinoma patients previously treated with IL2. Eur. J. Cancer. 30A, 1078 (1994).
  41. Ishikawa, E., Tsuboi, K., Saijo, K., Harada, H., Takano, S., Nose, T. and Ohno, T. : Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer. Res. 24, 1861 (2004).
  42. Carlens, S., Gilljam, M., Chambers, B. J., Aschan, J., Guven, H., Ljunggren, H. G., Christensson, B. and Dilber, M. S. : A new method for in vitro expansion of cytotoxic human CD3-CD56+ natural killer cells. Hum. Immunol. 62, 1092 (2001). https://doi.org/10.1016/S0198-8859(01)00313-5
  43. Klingemann, H. G. : Natural killer cell-based immunotherapeutic strategies. Cytotherapy 7, 16 (2005). https://doi.org/10.1080/14653240510018000
  44. Alici, E., Sutlu, T., Björkstrand, B., Gilljam, M., Stellan, B., Nahi, H., Quezada, H. C., Gahrton, G., Ljunggren, H. G. and Dilber, M.S. Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components. Blood. 111, 3155 (2008). https://doi.org/10.1182/blood-2007-09-110312
  45. Guven, H., Gilljam, M., Chambers, B. J., Ljunggren, H. G., Christensson, B., Kimby, E. and Dilber, M.S. : Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. Leukemia. 17, 1973 (2003). https://doi.org/10.1038/sj.leu.2403083
  46. Alici, E., Konstantinidis, K. V., Sutlu, T., Aints, A., Gahrton, G., Ljunggren, H. G. and Dilber, M. S. : Anti-myeloma activity of endogenous and adoptively transferred activated natural killer cells in experimental multiple myeloma model. Exp. Hematol. 35, 1839 (2007). https://doi.org/10.1016/j.exphem.2007.08.006
  47. Basse, P. H., Whiteside, T. L. and Herberman, R. B. : Cancer immunotherapy with interleukin-2-activated natural killer cells. Mol. Biotechnol. 21, 161 (2002). https://doi.org/10.1385/MB:21:2:161
  48. Siegler, U., Kalberer, C. P., Nowbakht, P., Sendelov, S., Meyer-Monard, S. and Wodnar-Filipowicz, A. : Activated natural killer cells from patients with acute myeloid leukemia are cytotoxic against autologous leukemic blasts in NOD/SCID mice. Leukemia. 19, 2215 (2005). https://doi.org/10.1038/sj.leu.2403985
  49. deMagalhaes-Silverman, M., Donnenberg, A., Lembersky, B., Elder, E., Lister, J., Rybka,W., Whiteside, T. and Ball, E. : Posttransplant adoptive immunotherapy with activated natural killer cells in patients with metastatic breast cancer. J. Immunother. 23, 154 (2000). https://doi.org/10.1097/00002371-200001000-00018
  50. Terunuma, H., Deng, X., Dewan, Z., Fujimoto, S. and Yamamoto, N. : Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections. Int. Rev. Immunol. 27, 93 (2008). https://doi.org/10.1080/08830180801911743