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

R G Uzzo1, P Rayman, V Kolenko

  • 1Department of Immunology, Lerner Research Institute, Cleveland, Ohio 44195, USA.

The Journal of Clinical Investigation
|September 24, 1999
PubMed

Insights

Tumor-derived gangliosides suppress T cell activation in renal cell carcinoma (RCC) patients by inhibiting nuclear factor-kappaB (NFkappaB) signaling. This impairment may blunt the body's antitumor immune response.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Activation of the transcription factor nuclear factor-kappaB (NFkappaB) is crucial for T cell function.
  • NFkappaB activation is frequently impaired in T cells from patients with renal cell carcinomas (RCCs).

Purpose of the Study:

  • To investigate the mechanism by which tumor-derived factors suppress T cell NFkappaB activity in RCC.
  • To identify the nature of the inhibitory agent produced by RCC.

Main Methods:

  • Cultured RCC explants and T cells from healthy volunteers were used to assess NFkappaB activity.
  • Analysis of tumor-derived soluble products, including sensitivity to enzymatic and physical treatments, and molecular weight determination.
  • Detection and characterization of gangliosides in tumor supernatants.
  • Assay of NFkappaB binding activity and cytokine expression (IL-2, IFN-gamma) after treatment with gangliosides.

Main Results:

  • Tumor-derived soluble products from RCC explants inhibited NFkappaB activity in T cells.
  • The inhibitory agent was identified as a ganglioside, characterized by sensitivity to neuraminidase, hydrophobicity, and molecular weight < 3 kDa.
  • Gangliosides were detected in RCC supernatants but not in normal kidney tissue.
  • Prepared gangliosides suppressed NFkappaB binding activity and reduced IL-2 and IFN-gamma expression in T cells.

Conclusions:

  • Tumor-derived gangliosides are responsible for inhibiting NFkappaB activity in T cells from RCC patients.
  • These gangliosides may play a significant role in blunting antitumor immune responses in RCC by impairing T cell function.

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