GM2 Expression in Renal Cell Carcinoma: Potential Role in Tumor-Induced T-Cell Dysfunction

Abstract

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-; 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 Mg/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-; production induced by RCC tissue-derived gangliosides, suggesting that GM2 plays a role in down-regulating cytokine production by CD4 + T cells. (Cancer Res 2006; 66(13): 6816-25)

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Such evolved tumor cells carry massive genetic alterations and are therefore able to suppress all steps of immune action, namely, the recruitment of, engagement by and function of cytolytic cells. [59][60][61][62] Additional tumor-extrinsic criteria, such as the genotype of the patient, can also impact the clinical outcome. Efficacy of the treatment in the relapsing follicular lymphoma patients was expected to result from the enhancement of ADCC by rituximab/ BrHPP/IL-2 co-administration.…”

TNF-α Induction of GM2 Expression on Renal Cell Carcinomas Promotes T Cell Dysfunction

“…The in vivo relevance of this observation stems from our determination that 19 of the 24 fresh RCC tumors we assessed were GM2 positive (14). Although TNF is most often considered in the context of its essential role in both innate and adaptive immune responses (15), it was originally described as an endotoxin-induced, macrophage-derived protein capable of mediating tumor necrosis (16).…”

Analysis of Renal Cell Carcinoma as a First Step for Developing Mass Spectrometry-Based Diagnostics

“…Of particular importance, PESI is very good at detecting the lipid components in human tissues and living animals [10]. Taking into account the fact that cancer calls display changes in lipid composition [13], such as phospholipids [14], sphingolipids [15,16], and cholesterol sulfates [17], we focused on determining the differences in lipid composition in cancer tissue for diagnoses of human renal cell carcinoma (RCC). We were able to delineate clear differences in spectral patterns with special references to lipids.…”