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Elevated Levels of Select Gangliosides in T Cells from Renal Cell Carcinoma Patients Is Associated with T Cell Dysfunction¹

Soumika Biswas,^* Kaushik Biswas,^* Amy Richmond, Jennifer Ko,^* Sankar Ghosh,^* Matthew Simmons, Patricia Rayman,^* Brian Rini, Inderbir Gill, Charles S. Tannenbaum,^* and James H. Finke^2*

^*Department of Immunology and Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation; Cleveland, OH 44195; Department of Solid Tumor, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 44195; and Department of Urology, Keck School of Medicine, University of Southern California 90089

Increased expression of gangliosides by different tumor types including renal cell carcinoma (RCC) is thought to contribute to the immune suppression observed in cancer patients. In this study, we report an increase in apoptotic T cells from RCC patients compared with T cells from normal donors that coincided with the detection of T cells staining positive for GM2 and that the apoptosis was predominantly observed in the GM2⁺ but not the GM2^– T cell population. Ganglioside shedding from tumor rather than endogenous production accounts for GM2⁺ T cells since there was no detectable level of mRNA for GM2 synthase in RCC patient T cells and in T cells from normal healthy donors after incubation with either purified GM2 or supernatant from RCC cell lines despite their staining positive for GM2. Moreover, reactive oxygen species as well as activated caspase 3, 8, and 9 were predominantly elevated in GM2⁺ but not GM2^– T cells. Similarly, increased staining for GD2 and GD3 but not GD1a was detected with patient T cells with elevated levels of apoptosis in the GD2⁺ and GD3⁺ cells. These findings suggest that GM2, GD2, and GD3 play a significant role in immune dysfunction observed in RCC patient T 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 R01-CA56937 (to J.H.F.), CA116255 (to J.H.F.), and CA111917 (to C.S.T.) and the Frank Rudy Fund for Cancer Research.

² Address correspondence and reprint requests to Dr. James H. Finke, Department of Immunology, NE4-307, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail address: finkej{at}ccf.org

³ Abbreviations used in this paper: TIL, tumor-infiltrating lymphocyte; RCC, renal cell carcinoma; FLICA, fluorochrome inhibitors of caspase; 7-AAD, 7-aminoactinomycin D; NKE, normal kidney epithelial; ROS, reactive oxygen species.