There is growing evidence to suggest that the immune dysfunction noted in T cells from cancer patients may be linked to the ability of tumors to alter the sensitivity of T cells to apoptosis. This idea is supported by our observation that a subset of tumor infiltrating T cells (TIL) is apoptotic, and that an even higher percentage of the viable TIL demonstrates a heightened sensitivity to activation induced cell death (AICD). Similar findings have been observed by others in different tumor types, and can also be seen in circulating T lymphocytes. We have also found that supernatants derived from renal cell carcinoma (RCC) explants can either directly induce apoptosis of peripheral blood T cells from normal individuals or sensitize them to AICD. Our recent findings implicate gangliosides within the tumor supernatants as one class of products that can induce both phenotypes in T cells. Gangliosides isolated from some RCC supernatants induce apoptosis, while gangliosides isolated from other RCC supernatants only sensitize T cells to AICD. Additional evidence suggests that gangliosides expressed on RCC lines induce T cell apoptosis. We have also found that aldehyde products of fatty acid oxidation, likely resulting from oxidative stress within the tumor microenvironment, represent another class of products within RCC supernatants that can induce apoptosis of T cells. Among the most prominent aldehyde products is 4-hydroxynonenal (HNE), which is present in our tumor supernatants. Moreover, commercial HNE can induce apoptosis of T cells. We propose that the heterogeneous capacity of RCC tumors to directly induce apoptosis, or sensitize T cells to AICD, is related to the variations in the specific products expressed by individual tumors. We further hypothesize that specific structural features of these molecules dictate whether individual products induce apoptosis or only sensitize. Thus, in Aim 1, we will determine the relationship between the structural characteristics and functional activities of these molecules. Other studies will determine the impact that blocking the formation of oxidative products or ganglioside synthesis in the RCC explants has on structure and function of apoptogenic and sensitizing products present in the tumor supernatants.
Aim 2 will determine whether apoptogenic gangliosides and HNE induce cell death via similar or distinct mechanisms. This will include testing whether these products differ in the reactive oxygen species (ROS) they induce, the order of signaling events they activate, and their ability to down regulate Bcl-2. Other experiments will determine the mechanism by which gangliosides sensitize T cells AICD. This will involve defining the effect that sensitizing gangliosides have on mitochondrial stability. A better understanding of immune dysfunction may lead to ways in which to improve anti-tumor immunity.
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