Impaired activation of NFΚB in T cells from a subset of renal cell carcinoma patients is mediated by inhibition of phosphorylation and degradation of the inhibitor, IΚBα

Activation of the transcription factor NF kappa B in peripheral blood T cells from patients with renal cell carcinoma (RCC) is compromised. This impaired signaling function results from a failure of RerA and c-Rel to translocate to the nucleus though normal levels of Rel proteins are present in the cytoplasm. We demonstrate here in a subset of BCC patients that the defect in NF kappa B activation is attributable to the absence of phosphorylation and degradation of The inhibitor I kappa B alpha. In patient T cells there was no stimulus dependent decrease in the cytoplasmic level of I kappa B alpha. Coimmunoprecipitation studies showed that RelA was in complex with I kappa B alpha and was not released after stimulation. Moreover, the phosphorylated form of I kappa B alpha detected in normal T cells after activation is absent in patient T cells. Additional experiments showed that soluble products from RCCs (RCC-S) can reproduce the same phenotype in T cells from healthy individuals. Supernatant fluid from cultured explants of RCC, but not normal kidney, inhibited the stimulus dependent nuclear translocation of NF kappa B without altering the cytoplasmic levels of RelA, c-Rel, and NF kappa B1. Phosphorylation and degradation of I kappa B alpha was also blocked by RCC-S, The mechanistic similarities between patient-derived T cells and normal T cells cultured with RCC-S suggest that the tumor-derived products may be the primary mediators of impaired T-cell function in this tumor system. (C) 1998 by The American Society of Hematology.