Lung cancer is the leading cause of cancer deaths in the United States. Despite the existing treatments for lung cancer, the long term survival of patients remains low. Activation of CD4+ and CD8+ T cells offers a promising approach for the treatment of cancer patients. My project focuses on developing a novel vaccine (MHC II vaccines) designed to activate tumor-reactive CD4+ T cells. MHC II vaccines are lung cancer cells transfected with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because active immunotherapies will only be effective if recipients are immuno-competent, we have tested if the vaccines activate CD4+ T cells from patients who have elevated levels of myeloid-derived suppressor cells (MDSC), a suppressor cell population that inhibit both innate and adaptive immunity. I demonstrate that MHC II vaccines activate tumor specific CD4+ T cells from the blood of healthy donors and lung cancer patients despite the presence of MDSC. Various mechanisms of immune suppression have been attributed to MDSC, however MDSC is an emerging field many more mechanisms are under their way. I have found a new mechanism through which MDSC block T cell proliferation by sequestering cysteine, an essential amino acid for T cells. T cells require cysteine because they lack cystathionase which converts methionine to cysteine, and because they do not have an intact xc- transporter and therefore cannot import cystine and reduce it intracellularly to cysteine. T cells depend on antigen presenting cells (APC) to export cysteine which is imported by T cells via their ASC neutral amino acid transporter. MDSC express the x c- transporter and import cystine; however, they do not express the ASC transporter and do not export cysteine. APC and MDSC compete for extracellular cystine, and in the presence of MDSC, APC release of cysteine is reduced, thereby limiting the extracellular pool of cysteine. Therefore, MDSC deplete cysteine for T cells and block their proliferation.
Therefore, MHC II vaccines may be used to treat immune suppressed lung cancer patients. Furthermore, provision of stable form of cysteine along with MHC II vaccines could further enhance the effectiveness of these vaccines.
|Commitee:||Alexander, Richard B., Bieberich, Charles J., Edelman, Martin J., Leips, Jeff W.|
|School:||University of Maryland, Baltimore County|
|School Location:||United States -- Maryland|
|Source:||DAI-B 70/09, Dissertation Abstracts International|
|Subjects:||Cellular biology, Immunology|
|Keywords:||Immune suppression, Lung cancer, MHC II vaccines, Myeloid-derived suppressor cells, T cell activation|
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