GM2 expression in renal cell carcinoma: potential role in tumor-induced T-cell dysfunction.
Multiple mechanisms have been proposed to account for immune escape by tumors. Although gangliosides have long been known to suppress T-cell immunity, few studies have examined the effect of human tumor-derived gangliosides on immune responses. Here, we show that gangliosides isolated from renal cell carcinoma (RCC) cell lines and clear cell tumor tissue can induce apoptosis in peripheral blood T cells. The RCC tissue-derived gangliosides also suppressed IFN-gamma and, in many cases, interleukin-4 production by CD4+ T cells at concentrations (1 ng/mL-100 pg/mL) well below those that induce any detectable T-cell death (4-20 microg/mL). Additional findings show that GM2 expressed by RCC plays a significant role in promoting T-cell dysfunction. This is supported by the demonstration that all RCC cell lines examined (n = 5) expressed GM2 as did the majority of tumors (15 of 18) derived from patients with clear cell RCC. Furthermore, an antibody specific for GM2 (DMF10.167.4) partially blocked (50-60%) T-cell apoptosis induced by coculturing lymphocytes with RCC cell lines or with RCC tissue-derived gangliosides. DMF10.167.4 also partially blocked the suppression of IFN-gamma production induced by RCC tissue-derived gangliosides, suggesting that GM2 plays a role in down-regulating cytokine production by CD4+ T cells.
Biswas
Kaushik
K
Department of Immunology and Mass Spectrometry Core, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Richmond
Amy
A
Rayman
Patricia
P
Biswas
Soumika
S
Thornton
Mark
M
Sa
Gaurisankar
G
Das
Tanya
T
Zhang
Renliang
R
Chahlavi
Ali
A
Tannenbaum
Charles S
CS
Novick
Andrew
A
Bukowski
Ronald
R
Finke
James H
JH
D017209:Apoptosis / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005678:G(M2) Ganglioside / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D005678:G(M2) Ganglioside