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Gangliosides Expressed by the Renal Cell Carcinoma Cell Line SK-RC-45 Are Involved in Tumor-induced Apoptosis of T Cells¹

Departments of Immunology [D. K., P. R., M. T., C. T., J. H. F.] and Cell Biology [C. H., M. C.] in the Lerner Research Institute, Experimental Therapeutics [R. M. B., J. H. F.], and Urological Institute [R. M. B., J. H. F.], Cleveland Clinic Foundation, Cleveland, Ohio 44195

It is now understood that the genetic plasticity of cancer cells can lead to alterations that confer selective growth advantages to the tumor, some of which play a role in immune escape. A number of mutations veiling tumor cells from host immune defenses have been well characterized but more recent studies suggest that a variety of tumors can also express products that are actually toxic for the immune effectors. A component of this tumor-induced T-cell death has been attributed to receptor-mediated apoptosis. Some tumors, however, synthesize soluble factors that mediate similar effects. In this regard, we previously showed that supernatants from explanted renal cell carcinoma (RCC) tumors sensitized normal T cells to activation induced cell death, and the responsible products had the features of gangliosides. We have also shown that renal tumor lines, including SK-RC-45, induce apoptosis of both Jurkat cells and normal T lymphocytes. Here, we used the ganglioside synthesis inhibitor PPPP to define the role of gangliosides in RCC cell line (SK-RC-45)-mediated T cell and Jurkat cell apoptosis and to elucidate the proapoptotic molecular events by which the glycosphingolipids produce their effects. The ganglioside-synthesizing SK-RC-45 line stimulated the TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labeling) positivity of cocultured T cells by a mechanism that involved decreasing lymphocyte expression levels of Bcl-2 and Bcl-_XL, inducing cytochrome c release from their mitochondria and activating caspases 9 and 3. These proapoptotic events were partially or completely abrogated when tumor cells were pretreated with PPPP for 5 days before the SK-RC-45/T lymphocyte coincubation, a regimen that reduced tumor-associated ganglioside levels by 70–80%. Our results suggest that gangliosides may be key mediators of RCC-induced T-cell apoptosis and imply that they contribute to the T-cell dysfunction in the tumor microenvironment.

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