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GM1 and Tumor Necrosis Factor-, Overexpressed in Renal Cell Carcinoma, Synergize to Induce T-Cell Apoptosis

¹ Molecular Medicine Division, Bose Institute, Kolkata, India; ² Department of Immunology, Lerner Research Institute and ³ Experimental Therapeutics, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio

Requests for reprints: Charles Tannenbaum, Department of Immunology/NE4-308, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: 216-445-0575; Fax: 216-444-9329; E-mail: tannenc{at}ccf.org.

Key Words: Apoptosis • Tumor immunity • T-lymphocytes • Gangliosides • TNF • GM1

The ability to induce T-cell apoptosis is one mechanism by which tumors evade the immune system, although the molecules involved remain controversial. We found that renal cell carcinoma (RCC)–induced T-cell apoptosis was inhibited by >50% when cocultures were performed with ganglioside-depleted tumor cells, caspase-8–negative lymphocytes, or anti–tumor necrosis factor- (TNF) antibodies, suggesting that tumor gangliosides synergize with signals delivered through TNF death receptors to mediate T-cell killing. The synergy between tumor-derived TNF and the RCC-overexpressed ganglioside GM1 for killing resting T cells is corroborated by studies using purified GM1 and rTNF, which indicate that a 48-hour pretreatment with the ganglioside optimally sensitizes the lymphocytes to a TNF-induced apoptotic death. However, activated T cells, which synthesize TNF themselves, can be killed by exogenous GM1 alone. RelA-overexpressing lymphocytes are protected from GM1 plus TNF-mediated apoptosis, a finding consistent with our previous studies indicating that gangliosides inhibit nuclear factor-B activation. These results are clinically relevant because, similar to T-cells cocultured with GM1-overexpressing RCC lines, T cells isolated from the peripheral blood of patients with metastatic RCC are also heavily coated with that tumor-shed ganglioside. This population of patient cells, unlike T cells isolated from normal donors, is highly susceptible to apoptosis induced by rTNF or by metastatic patient sera, which contain elevated levels of the cytokine. This report thus extends our previous studies by demonstrating that tumor-derived TNF enhances RCC apoptogenicity not only by inducing ganglioside synthesis but also by initiating receptor-dependent apoptosis in T cells in which the nuclear factor-B activation pathway has been inhibited by GM1. [Cancer Res 2008;68(6):2014–23]

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