Renal cell carcinoma-derived gangliosides suppress nuclear factor-κB activation in T cells

Activation of the transcription factor nuclear factor-kappa B (NF kappa B) is impaired in T cells from patients with renal cell carcinomas (RCCs). In circulating T cells from a subset of patients with RCCs, the suppression of NF kappa B binding activity is downstream from the stimulus-induced degradation of the cytoplasmic factor I kappa B alpha. Tumor-derived soluble products from cultured RCC explants inhibit NF kappa B activity in T cells from healthy volunteers, despite a normal level of stimulus-induced I kappa B alpha degradation in these cells. The inhibitory agent has several features characteristic of a ganglioside, including sensitivity to neuraminidase but not protease treatment; hydrophobicity; and molecular weight less than 3 kDa. Indeed, we detected gangliosides in supernatants from RCC explants and not from adjacent normal kidney tissue. Gangliosides prepared from RCC supernatants, as well as the purified bovine gangliosides G(m1) and G(d1a), suppressed NF kappa B binding activity in T cells and reduced expression of the cytokines IL-2 and IFN-gamma. Taken together, our findings suggest that tumor-derived gangliosides may blunt antitumor immune responses in patients with RCCs.