HLA-class-I and -class-II expression on renal tumor xenografts and the relation to sensitivity for alpha-IFN, gamma-IFN and TNF.
In this study we evaluated the usefulness of the histocompatibility leucocyte antigen (HLA) class-I and class-II expression on renal-cell carcinoma (RCC) xenografts as predictive markers for response to cytokine therapy. Eight different RCC xenografts growing in BALBC nu/nu mice were treated with 0.5 or 5.0 ng/g recombinant human alpha- or gamma-interferon (IFN), or 500 ng/g recombinant human tumor necrosis factor (TNF). Modulation of HLA class-I, -II expression was evaluated immunohistochemically using the monoclonal antibodies (MAbs) W6.32 and B8.11.2 and at the mRNA level using the plasmids pDP001 and DR alpha 120. HLA class-I expression in all lines was upregulated by alpha- and gamma-IFN and was highest in the high-IFN-dose-treated tumors. TNF also stimulated HLA-class-I expression and up-regulated class-I expression still further when combined with IFN. Highest up-regulation of HLA-class-I in all tumors was measured in the alpha-IFN-5.0/TNF-500-ng/g-treated mice, although this was not necessarily the treatment regimen resulting in the most pronounced effect on tumor growth. Hence, maximum upregulation of class-I antigens at a given regimen was not always indicative for the highest achievable anti-tumor effect. HLA-class-II expression which was present on only 3 of the untreated tumors was up-regulated by both alpha and gamma-IFN. TNF itself did not up-regulate class-II expression but enhanced the class-II expression on the alpha-IFN-treated tumors but not on the gamma-IFN-treated tumors. Irrespective of the basic expression level, inducibility of both HLA-class-I and -class-II antigens appear to be correlated to the direct effects on growth of renal-tumor xenografts towards alpha-IFN, gamma-IFN and TNF. Modulation of HLA antigens was studied in the nude mouse, hence T-cell-mediated effector mechanisms cannot explain the good correlation between inducibility and response. Nonetheless, our studies indicate that the extent of modulation of HLA-class-I and -II can serve as predictive marker for response to cytokine therapy, which may serve as a valuable criterion for inclusion of patients in cytokine treatment regimens.
Beniers
A J
AJ
Department of Urology, University Hospital Nijmegen, The Netherlands.
Peelen
W P
WP
Debruyne
F M
FM
Schalken
J A
JA
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005805:Genes, MHC Class I / Q000187:drug effects; D005802:Genes, MHC Class II / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007370:Interferon Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma