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 NFκB in peripheral blood T cells from patients with renal cell carcinoma (RCC) is compromised. This impaired signaling function results from a failure of ReIA and c-ReI to translocate to the nucleus though normal levels of ReI proteins are present in the cytoplasm. We demonstrate here in a subset of RCC patients that the defect in NFκB activation is attributable to the absence of phosphorylation and degradation of the inhibitor IκB2a. In patient T cells there was no stimulus dependent decrease in the cytoplasmic level of IκBα. Coimmunoprecipitation studies showed that RelA was in complex with IκBα and was not released after stimulation. Moreover, the phosphorylated form of IκBα 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 NFκB without altering the cytoplasmic levels of ReIA, c-ReI, and NFκB1. Phosphorylation and degradation of IκBα 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.