Abstract
Circulating immune markers sICAM-1, sELAM-1, sMHC-I, β2-MG, sCD4 and sCD8 were evaluated prior to and during immunotherapy with biologically active doses of interferon gamma (IFN-γ) in 16 patients with advanced renal cell carcinoma (RCC) over a period of 12 months. Compared to 20 healthy controls, significantly (P < 0.01) elevated baseline levels of circulating adhesion molecules sICAM-1 (mean 1166 vs 230 ng/ml) and sELAM-1 (70 vs 17 ng/ml) were found in all patients. Compared to responders (n = 2) or patients with stable disease (n = 2), progressive disease during therapy (n = 12) was associa ed with significantly (P < 0.05) higher mean concentrations of sICAM-1 (1574 vs 962 ng/ml) and sELAM-1 (86 vs 46 ng/ml). Pretherapeutic and intratherapeutic levels of sMHC-I among the RCC patients were significantly (P < 0.05) lower than among the controls (0.41 vs 0.8 ng/ml). sCD4 levels clearly showed the same tendency (24 vs 33 U/l). sCD8 baseline levels, by contrast, were significantly (P < 0.05) elevated (564 vs 336 U/l), reflecting either activation of the NK-cell subset or increased synthesis of CD8 + T-suppressor cells. Again, significantly (P < 0.05) higher intratherapeutic sCD8 concentrations were observable with progressive disease than with response to therapy or stable disease (721 vs 355 U/l). Interestingly, although the biologically active dose of IFN-γ was defined by an increase in β2-MG release of at least 30% within 48 h after injection, none of the other markers showed any significant alteration following IFN-γ administration, suggesting that IFN-γ in vivo does not produce changes in circulating markers of activation that might be expected on the basis of its effects in vitro. The finding of significantly elevated concentrations of sICAM-1, sELAM-1 and sCD8 in the presence of low sCD4 and sMHC-I levels might be of clinical significance for indicating ongoing tumor progression.
Similar content being viewed by others
References
Aulitzky W, Gastl G, Aulitzky WE, Nachbaur K, Lanske B, Kemmler G, Flener R, Frick J, Huber C (1987) Interferon-γ for the treatment of metastatic renal cancer: dose-dependent stimulation and down regulation of beta 2 microglobulin and neopterin responses. Immunobiology 176:85
Ball ED, Guyre PM, Glynn JM, Rigby WFC, Fanger MW (1984) Modulation of class I HLA antigens on HL-60 promyelocytic leukemia cells by serum-free medium: re-induction by γ-IFN and 1,25-dihydroxyvitamin D3 (calcitriol). J Immunol 132:2424
Banner BF, Burnham JA, Bahnson RR, Ernstoff MS, Auerbach HE (1990) Immunophenotypic markers in renal cell carcinoma. Mod Pathol 3:129
Bichler KH, Kleinknecht S, Strohmaier WL (1990) Immune status and immune therapy of renal cell carcinoma. Urol Int 45:269
Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA (1986) Induction by IL 1 and interferon-γ: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol 137:245
Flyer DC, Burakoff SJ, Faller DV (1985) Retrovirus induced changes in major histocompatibility complex antigen expression influence suscepibility to lysis by cytotoxic T lymphocytes. J Immunol 135:2287
Grups JW, Frohmüller HGW (1990) Influence of cyclic interferon gamma and lymphocytes and their subpopulations in patients with renal carcinoma. Urology 35:111
Halloran PF, Jephthah-Ochola J, Urmson J, Farkas S (1985) Systemic immunologic stimuli increase class I and II antigen expression in mouse kidney. J Immunol 135, 2:1053
Halloran PF, Wadgymar A, Autenried P (1986) The regulation of expression of major histocompatibility complex products. Transplantation 41:413
Hammerling GJ, Wallich R, Bulbuc N, Katzav S, Segal S, Feldman M (1985) Abrogation of metastatic properties of tumor cells by de novo expression of H-2K antigens following H-2 gene transfection. Nature 315:301
Harning R, Maninolfi E, Bystryn JC, Henn M, Merluzzi VJ, Rothlein R (1991) Serum levels of circulating intercellular adhesion molecule 1 in human malignant melanoma. Cancer Res 51:5003
Heicappell R, Ackermann R (1990) Rationale for immunotherapy of renal cell carcinoma. Urol Res 18:357
Hession C, Osborn L, Goff D, Chi-Rosso G, Vassallo C, Pasek M, Pittack C, Tizard R, Goetz S, McCarthy K, Hopple S, Lobb R (1990) Endothelial leukocyte adhesion molecule 1: direct expression cloning and functional interactions. Proc Natl Acad Sci USA 87:1673
Ho AD, Grossman M, Trümper L, Pezzutto A, Pralle H, Boedewadt-Radzun S, Papendick U, Göd B, Zwingers T, Hunstein W (1990) Clinical implications of increased plasma levels of CD8 in patients with hairy cell leukemia. Blood 75:1119
Johnson JP, Stade BG, Holzmann B, Schwable W, Riethmuller G (1989) De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis. Proc Natl Acad Sci 86:641
Killander D, Lindhal P, Lundin L, Leary P, Gresser I (1976) Relationship between the enhanced expression of histocompatibility antigens on interferon-treated L1210 cells and their position in the cell cycle. Eur J Immunol 6:56
Kyan-Aung U, Haskard DO, Poston RN, Thornhill MH, Lee TH (1991) Endothelial leukocyte adhesion molecule-1 and intercellular adhesion molecule-1 mediate the adhesion of eosinophils to endothelial cells in vitro and are expressed by endothelium in allergic cutaneous inflammation in vivo. J Immunol 146:521
Meuer SC, Schlossman SF, Reinherz E (1982) Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions. Proc Natl Acad Sci USA 79:4395
Minervini R, Panichi V, Vigano L, Felipetto R, Gattai V, Cecchi M, Fiorentini L, Palla R (1994) Cellular expression of lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 in normal kidney structures and in renal cancer. Eur Urol 26:103
Mukherji B, Ergin MT, Guha A, Tatake RT, Nashed AL (1986) Suppressor cell activities in autologous human tumor systems: suppression of tumor immunity. Arch Surg 121:1404
Munro JM, Pober JS, Cotran RS (1991) Recruitment of neutrophils in the local endotoxin response: association with de novo endothelial expression of endothelial leukocyte adhesion molecule-1. Lab Invest 64:295
Nachbaur K, Troppmair J, Kotlan B, König P, Aulitzky W, Bieling B, Huber Ch (1988) Cytokines in the control of β2-microglobulin release: II. In vivo studies with recombinant interferons and antigen. Immunobiol 177:66
Natali P, Nicotra MR, Cavaliere R, Bigotti A, Romano G, Temponi M, Ferrone S (1990) Differential expression of intercellular adhesion molecule 1 in primary and metastatic lesions. Cancer Res 50:1271
Nathan CF, Prendergast TJ, Wiebe ME, Stanley ER, Platzer E, Remold HG, Welte K, Rubin BY, Murray HW (1984) Activation of human macrophages. Comparison of other cytokines with interferon gamma. J Exp Med 160:600
Pfizenmaier K, Bartsch H, Scheurich P, Selinger B, Ucer U, Vehmeyer K, Nagel GA (1985) Differential γ-interferon response of human colon carcinoma cells: inhibition of proliferation and modulation of immunogenicity as independent effects of γ-interferon on tumor cell growth. Cancer Res 45:3503
Pober JS, Gimbrone MA, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, Springer TA (1986) Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol 137:1893
Potocnik AJ, Kinne R, Menninger H, Zacher J, Emmerich F, Kroczek RA (1990) Expression of activation antigens on T cells in rheumatoid arthritis patients. Scand J Immunol 31:213
Pui CH, Ip SH, Dodge RK, Carrabis S, Brown M, Crist WM, Berard CW, Kung P, Dahl GV, Murphy SB (1988) Serum-levels of CD8 antigen in childhood lymphoid malignancies: a possible indicator of increased suppressor cell activity in poor-risk patients. Blood 73:1015
Pui CH, Ip SH, Thompson E, Dodge RK, Brown M, Wiliams J, Carrabis S, Kung P, Berard CW, Crist WM (1989) Increased serum CD8 antigen level in childhood Hodgkins's disease relates to advanced stage and poor treatment outcome. Blood 73, 1:209
Reinherz EL, Schlossman SF (1980) The differentiation and function of human T lymphocytes. Cell 19:821
Von Roenn J, Harris JE, Braun DP (1987) Suppressor cell function in solid tumor cancer patients. J Clin Oncol 5:150
Rothlein R, Czajkowski M, O'Neill MM, Marlin SD, Mainolfi E, Merluzzi VJ (1988) Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-inflammatory cytokines. J Immuno 141:1665
Tanaka K, Yoshioka T, Bieberich C, Jay G (1988) Role of the major histocompatibility complex class I antigens in tumor growth and metastasis. Ann Rev Immunol 6:359
Taniguchi K, Kaerre K, Klein G (1985) Lung colonization and metastasis by disseminated B 16 melanoma cells: H-2 associated control at the level of the host and tumor cell. Int J Cancer 36:503
Tomita Y, Nishiyama T, Fujiwara M, Sato S (1990) Immunohistochemical detection of major histocompatibility complex antigens and quantitative analysis of tumor-infiltrating mononuclear cells in renal cell cancer. Br J Urol 62:354
Vanky F, Wang P, Patarroyo M, Klein E (1990) Expression of adhesion molecule ICAM-1 and major histocompatibility complex class I antigens on human cells is required for their interaction with autologous lymphocytes in vitro. Cancer Immunol Immunother 31:19
Vibe-Peterson J, Tvede N, Diamant M, Kjerulff AA, Sorensen HR (1991) Soluble interleukin-2 receptor and soluble CD8 antigen levels in serum from patients with non-resectable lung cancer. Cancer Immunol Immunoter 33:121
Weiner LM, Steplewski Z, Koprowski H, Litwin S, Comis RL (1988) Divergent dose related effects of γ-interferon therapy on in vitro antibody-dependent cellular and nonspecific cytotoxicity by human peripheral blood monocytes. Cancer Res 48:1042
Zembala M, Mytar B, Popiela T, Asherson GL (1977) Depressed in vitro peripheral blood lymphocyte response to mitogens in cancer patients: the role of suppressor cells. Int J Cancer 19:605
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Höbarth, K., Hallas, A., Steiner, G. et al. Circulating immune markers in advanced renal cell carcinoma during immunotherapy with interferon gamma. Urol. Res. 24, 101–106 (1996). https://doi.org/10.1007/BF00431087
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00431087