Alterations in NF B 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 NFκB 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 NFκB complexes, resulting in a loss of binding to κB sequences. NFκB 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-α) and receptor genes (11-13). The importance of NFκB activation in T-cell immunity has been documented using knockout mice where deletions of individual NFκB family members resulted in defective T- and B-cell functions (14,15). Current evidence suggests that NFκB is also important for cell survival because its activation may induce genes that protect T cells from apoptosis (16,17).