Alterations in NFkB Activation in T Lymphocytes of Patients With Renal Cell Carcinoma

T cells represent an important component in the development of an effective antitumor immune response. Although most solid tumors are infiltrated with T lymphocytes, including some clones capable of preferentially recognizing malignant cells, T-cell immunity fails to develop adequately in patients with tumors (1–4). Defects in proliferation and effector functions have been noted in peripheral blood T cells, while more pronounced alterations have been reported for T cells infiltrating the tumor (5,6). Moreover, cytokine gene expression normally associated with the development of an effective antitumor immune response is absent in the tumor (7). Alterations in expression and activity of intracellular signaling elements have been reported in T cells from patients with tumors (8). These include defective activation of the transcription factor NFkB in both tumor-bearing mice and patients with renal cell carcinoma (RCC) (9,10). The major problem appears to be an impaired nuclear accumulation of NFkB complexes, resulting in a loss of binding to kB sequences. NFkB plays an important role in the development of T-cell-mediated immune responses through its control of a diverse set of genes that include cytokines (interleukin 2 [IL-2] and tumor necrosis factor-a) and receptor genes (11–13). The importance of NFkB activation in T-cell immunity has been documented using knockout mice where deletions of individual NFkB family members resulted in defective Tand B-cell functions (14,15). Current evidence suggests that NFkB is also important for cell survival because its activation may induce genes that protect T cells from apoptosis (16,17). An important question to address is whether the tumor itself is responsible for impaired T-cell signaling. In animal models, tumor progression has been associated with reduced NFkB activation and kB-dependent gene expression (9); however, the cause of NFkB suppression in patients with cancer is not known. To address this issue, we performed several types of experiments. One set determined if removal of the tumor would result in normal NFkB activation in patients with previously defective T cells. Initial experiments characterized defects in NFkB signaling in three sets of patients: those with localized (n 4 46) or metastatic (n 4 42)