TNF-alpha induction of GM2 expression on renal cell carcinomas promotes T cell dysfunction.

Abstract

Previous studies from our laboratory demonstrated the role of tumor-derived gangliosides as important mediators of T cell apoptosis, and hence, as one mechanism by which tumors evade immune destruction. In this study, we report that TNF-alpha secreted by infiltrating inflammatory cells and/or genetically modified tumors augments tumor-associated GM2 levels, which leads to T cell death and immune dysfunction. The conversion of weakly apoptogenic renal cell carcinoma (RCC) clones to lines that can induce T cell death requires 3-5 days of TNF-alpha pretreatment, a time frame paralleling that needed for TNF-alpha to stimulate GM2 accumulation by SK-RC-45, SK-RC-54, and SK-RC-13. RCC tumor cell lines permanently transfected with the TNF-alpha transgene are similarly toxic for T lymphocytes, which correlates with their constitutively elevated levels of GM2. TNF-alpha increases GM2 ganglioside expression by enhancing the mRNA levels encoding its synthetic enzyme, GM2 synthase, as demonstrated by both RT-PCR and Southern analysis. The contribution of GM2 gangliosides to tumor-induced T cell death was supported by the finding that anti-GM2 Abs significantly blocked T cell apoptosis mediated by TNF-alpha-treated tumor cells, and by the observation that small interfering RNA directed against TNF-alpha abrogated GM2 synthase expression by TNF-transfected SK-RC-45, diminished its GM2 accumulation, and inhibited its apoptogenicity for T lymphocytes. Our results indicate that TNF-alpha signaling promotes RCC-induced killing of T cells by stimulating the acquisition of a distinct ganglioside assembly in RCC tumor cells.

• Authors: Gira Raval, Soumika Biswas, Patricia Rayman, Kaushik Biswas, Gaurisankar Sa, Sankar Ghosh, Mark Thornton, Cynthia Hilston, Tanya Das, Ronald Bukowski, James Finke, Charles S Tannenbaum
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 10 Pg. 6642-52 (May 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17475896 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Antibodies, Blocking
• Glycosides
• Tumor Necrosis Factor-alpha
• G(M2) Ganglioside

Topics

• Adjuvants, Immunologic (physiology)
• Antibodies, Blocking (pharmacology)
• Apoptosis (immunology)
• Carcinoma, Renal Cell (immunology, metabolism, pathology)
• Cell Line, Tumor
• G(M2) Ganglioside (biosynthesis, genetics, physiology)
• Gene Expression Regulation, Neoplastic (immunology)
• Glycosides (biosynthesis, physiology)
• Humans
• Kidney Neoplasms (immunology, metabolism, pathology)
• Resting Phase, Cell Cycle (immunology)
• T-Lymphocyte Subsets (cytology, immunology, metabolism, pathology)
• Transfection
• Tumor Escape (immunology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology, physiology)
• Up-Regulation (immunology)