HLA‐class‐I and‐class‐II expression on renal tumor xenografts and the relation to sensitivity for α‐IFN, γ‐IFN and TNF

Abstract

In this study we evaluated the usefulness of the histocom-patibility 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 at-or γ-interferon (If N), 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 α-and γ-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 up-regulation 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 a and γ-IFN. TNF itself did not up-regulate class-II expression but enhanced the class-II expression on the α-IFN-treated tumors but not on the γ-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 α-IFN, γ-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.