| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Induction of GM2 Expression on Renal Cell Carcinomas Promotes T Cell Dysfunction1
* Department of Immunology, Lerner Research Institute, and
Experimental Therapeutics, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 44195; and
Department of Animal Physiology, Bose Institute, Calcutta, India
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-
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- pretreatment, a time frame paralleling that needed for TNF- to stimulate GM2 accumulation by SK-RC-45, SK-RC-54, and SK-RC-13. RCC tumor cell lines permanently transfected with the TNF- transgene are similarly toxic for T lymphocytes, which correlates with their constitutively elevated levels of GM2. TNF- 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--treated tumor cells, and by the observation that small interfering RNA directed against TNF- 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- signaling promotes RCC-induced killing of T cells by stimulating the acquisition of a distinct ganglioside assembly in RCC tumor cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1-CA56937, CA90995, CA87644, and CA111917, and the Kidney Cancer Association Senior Investigator Award. Salary support for G.R. was provided by a gift from Frank Rudy (Los Angeles, CA).
2 Address correspondence and reprint requests to Dr. Charles S. Tannenbaum, Department of Immunology, NE4-308, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail address: Tannenc{at}ccf.org
3 Abbreviations used in this paper: PPPP, 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol; DAPI, 4',6'-diamidino-2-phenylindole; FasL, Fas ligand; LSA, lipid-bound sialic acid; siRNA, small interfering RNA; VHL, von Hippel-Lindau.
This article has been cited by other articles:
|
|
 |
|
  T. Das, G. Sa, E. Paszkiewicz-Kozik, C. Hilston, L. Molto, P. Rayman, D. Kudo, K. Biswas, R. M. Bukowski, J. H. Finke, et al. Renal Cell Carcinoma Tumors Induce T Cell Apoptosis through Receptor-Dependent and Receptor-Independent Pathways J. Immunol., April 1, 2008; 180(7): 4687 - 4696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Das, G. Sa, C. Hilston, D. Kudo, P. Rayman, K. Biswas, L. Molto, R. Bukowski, B. Rini, J. H. Finke, et al. GM1 and Tumor Necrosis Factor-{alpha}, Overexpressed in Renal Cell Carcinoma, Synergize to Induce T-Cell Apoptosis Cancer Res., March 15, 2008; 68(6): 2014 - 2023. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
