Objective To investigate the clinical significance of the expression of MHC class I chain-related gene A (MICA) in patients with advanced non-small cell lung cancer and explore the relationship between MICA expression and the efficacy of cytokine-induced killer cell (CIK) therapy for treating advanced non-small cell lung cancer. Methods We obtained data on 222 patients with advanced non-small cell lung cancer, including data on MICA expression, age, gender, ECOG score, pathological type, stage, treatment history (including 38 patients who were given autologous CIK cell infusion), and overall survival (OS). MICA expression in lung cancer tissue was evaluated by immunohistochemical staining. Analyses of MICA expression, and CIK therapy association with survival outcomes were performed using Cox proportional models, Kaplan-Meier methods, and the log-rank test. Result s MICA was expressed in both membrane and cytoplasm. MICA expression correlated with the stage of lung cancer, ECOG score, gender and age. Multivariate COX regression analysis showed that the expression of MICA was an independent prognostic factor of advanced non-small cell lung cancer (p = 0.002). In subgroup analysis, we divided the 222 patients into CIK and control groups. In the CIK group, the medium OS (mOS) of patients with a high expression of MICA was longer than in those with low expression of MICA (27 months vs. 13 months). In the control group, the mOS in patients with a high expression of MICA was shorter than in patients with low MICA expression (9 months vs. 18 months). COX regression analysis showed that the MICA expression affects the effect of CIK therapy (p<0.0001). Conclusion 1) The high expression of MICA is one of the indicators of a poor prognosis for advanced non-small cell lung cancer patients. 2) The high expression of MICA might be one of the predictive factors for successful CIK therapy.
References
[1]
Jemal A, Bray F (2011) Center MM, Ferlay J, Ward E, et al (2011) Global cancer statistics. CA Cancer J Clin 61: 69–90.
[2]
Stroncek D, Berlyne D, Fox B, Gee A, Heimfeld S, et al. (2010) Developments in clinical cell therapy. Cytotherapy 12: 425–428.
[3]
Kakimi K, Nakajima J, Wada H (2009) Active specific immunotherapy and cell-transfer therapy for the treatment of non-small cell lung cancer. Lung Cancer 65: 1–8.
[4]
Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IG (2011) Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 137: 305–310.
[5]
Dougan M, Dranoff G (2009) Immune therapy for cancer. Annu Rev Immunol 27: 83–117.
[6]
Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22: 329–360.
[7]
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, et al. (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285: 727–729.
[8]
Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, et al. (2003) Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102: 1389–1396.
[9]
Groh V, Steinle A, Bauer S, Spies T (1998) Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science 279: 1737–1740.
[10]
Gleimer M, Parham P (2003) Stress management: MHC class I and class I-like molecules as reporters of cellular stress. Immunity 19: 469–477.
[11]
Zamai L, Ponti C, Mirandola P, Gobbi G, Papa S, et al. (2007) NK cells and cancer. J Immunol 178: 4011–4016.
[12]
Pardoll DM (2001) Immunology. Stress, NK receptors, and immune surveillance. Science 294: 534–536.
[13]
Hayakawa Y, Kelly JM, Westwood JA, Darcy PK, Diefenbach A, et al. (2002) Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin. J Immunol 169: 5377–5381.
[14]
Friese MA, Platten M, Lutz SZ, Naumann U, Aulwurm S, et al. (2003) MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res 63: 8996–9006.
[15]
Salih HR, Rammensee HG, Steinle A (2002) Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 169: 4098–4102.
[16]
Shi M, Zhang B, Tang ZR, Lei ZY, Wang HF, et al. (2004) Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol 10: 1146–1151.
[17]
Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL (1991) Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 174: 139–149.
[18]
Schmidt-Wolf IG, Lefterova P, Mehta BA, Fernandez LP, Huhn D, et al. (1993) Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 21: 1673–1679.
[19]
Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS (2004) Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 103: 3065–3072.
[20]
Huang B, Sikorski R, Sampath P, Thorne SH (2011) Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer. J Immunother 34: 289–296.
[21]
Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, et al. (2008) NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28: 571–580.
[22]
Watson NF, Spendlove I, Madjd Z, McGilvray R, Green AR, et al. (2006) Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer 118: 1445–1452.
[23]
Madjd Z, Spendlove I, Moss R, Bevin S, Pinder SE, et al. (2007) Upregulation of MICA on high-grade invasive operable breast carcinoma. Cancer Immun 7: 17.
[24]
Li K, Mandai M, Hamanishi J, Matsumura N, Suzuki A, et al. (2009) Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: high expression of ULBP2 is an indicator of poor prognosis. Cancer Immunol Immunother 58: 641–652.
[25]
McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109: 716–721.
[26]
Busche A, Goldmann T, Naumann U, Steinle A, Brandau S (2006) Natural killer cell-mediated rejection of experimental human lung cancer by genetic overexpression of major histocompatibility complex class I chain-related gene A. Hum Gene Ther. 17: 135–146.
[27]
Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3: 781–790.
[28]
Lanier LL (2001) A renaissance for the tumor immunosurveillance hypothesis. Nat Med 7: 1178–1180.
[29]
Diefenbach A, Jensen ER, Jamieson AM, Raulet DH (2001) Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413: 165–171.
[30]
Xiao P, Xue L, Che LH, Peng JJ, Wu HX, et al. (2008) Expression and roles of MICA in human osteosarcoma. Histopathology 52: 640–642.
[31]
Groh V, Wu J, Yee C, Spies T (2002) Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419: 734–738.
[32]
Wang Y, Dai H, Li H, Lv H, Wang T, et al. (2011) Growth of human colorectal cancer SW1116 cells is inhibited by cytokine-induced killer cells. Clin Dev Immunol 2011: 621414.
[33]
Helms MW, Prescher JA, Cao YA, Schaffert S, Contag CH (2010) IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy. Cancer Immunol Immunother 59: 1325–1334.
[34]
Mesiano G, Todorovic M, Gammaitoni L, Leuci V, Giraudo DL, et al. (2012) Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. Expert Opin Biol Ther 12: 673–684.
