IFN-ALPHA THERAPY OF RENAL-CELL CARCINOMA - DEFECT OF LYMPHOCYTE SENSITIVITY TO MITOGENIC AND ACTIVATING CYTOKINE SIGNALS IN PATIENTS NOT-RESPONDING TO THERAPY

The present prospective study was designed to assess whether the renal cell carcinoma (RCC) patients treated with recombinant interferon alp ha (IFN alpha), whose tumours respond (responders) and do not respond (non-responders) to IFN alpha therapy, differ with regard to in vitro sensitivity of peripheral blood lymphocytes (PBL) to interleukin 2 (IL -2), IFN alpha, and IFN gamma signals prior to therapy. Twenty-one pat ients with advanced RCC after nephrectomy, 15 responders and 6 non-res ponders, were entered into a protocol. The protocol involved isolation and freezing of PBL samples followed by IFN alpha treatment of patien ts, assessment of proliferative and activating PBL responses, and eval uation of the therapeutic results. Freezing of PBL samples allowed us to compare the in vitro reactivity of PBL from individual RCC patients , repeatedly and under standard conditions. Substantial differences in proliferative responses to the mitogenic IL-2 signal of PBL derived f rom IFN alpha responders and nonresponders were found. Whereas the IL- 2-induced proliferative responses of PBL from normal blood donors and IFN alpha responders were comparable, the proliferative responses of P BL from IFN alpha non-responders were significantly decreased, suggest ing an immune dysfunction in non-responders. Cultivation of PBL from R CC patients in medium supplemented with IFN alpha increased the lytic activity of PBL from IFN alpha responders directed against RCC targets ; no such increase could be observed with non-RCC targets, with PBL fr om IFN alpha non-responders, or with PBL from normal blood donors. Det ection of phytohaemagglutinin (PHA)-stimulated IFN gamma secretion by PBL at the single cell level using enzyme-linked immunospot (ELISpot) assay revealed that the ability to produce IFN gamma was substantially decreased in IFN gamma non-reponders, as compared to IFN alpha respon ders and to normal blood donors.