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.