Research

It is now well-established that a major barrier to the development of effective immunotherapy for the treatment of renal cell carcinomas (RCC) and gliomas is the generation of T cell and dendritic cell dysfunction mediated by the tumor microenvironment. A major component of T cell dysfunction relates to increased sensitivity of T cells to apoptosis. Our recent findings suggest that gangliosides and oxidized lipid aldehydes make a significant contribution to sensitizing T cells to apoptosis.

One goal is to identify the individual gangliosides and oxidized lipid species within the tumor microenvironment that impair T cell survival utilizing HPLC and mass spectrometry. We have demonstrated that GM2 is overexpressed in RCC, is shed into the peripheral blood, and becomes associated with T cell plasma membranes and can mediate apoptosis. We plan to use the same approaches to define other gangliosides and oxidized lipids that contribute to T cell dysfunction.

Another focus is to define the mechanism by which gangliosides and oxidized lipids initiate T cell apoptosis. Our findings suggest that ganglioside-mediated T cell death results from induction of reactive oxygen species leading to mitochondrial damage that is further amplified by gangliosides-induced suppression of NFkB and activation of the JNK pathway. Studies are underway to understand how gangliosides impair NFkB activation and initiate JNK kinase phosphorylation.

Recently we found that T cell apoptosis induced by RCC lines and gangliosides can be blocked by the antioxidant, desferrioxamine (DFO). New studies will test whether DFO can promote T cell survival in tumor bearing mice and enhance antitumor activity initiated by dendritic cell-based vaccines.