Gangliosides expressed by the renal cell carcinoma cell line SK-RC-45 are involved in tumor-induced apoptosis of T cells.
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.
Kudo
Daisuke
D
Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Rayman
Patricia
P
Horton
Claudine
C
Cathcart
Martha K
MK
Bukowski
Ronald M
RM
Thornton
Mark
M
Tannenbaum
Charles
C
Finke
James H
JH
D017209:Apoptosis / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D018920:Coculture Techniques; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D005732:Gangliosides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011759:Pyrrolidines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C110417:1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D005732:Gangliosides; D011412:Propanolamines; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D051020:bcl-X Protein; D020169:Caspases