MHC II cell-based immunotherapy for non-small cell lung cancer in the presence of immune suppression.

Lung cancer is the leading cause of cancer deaths in the United States. Despite the existing treatments of surgery, radiotherapy, chemotherapy, and multimodal therapies, the long term survival of patients remains low. Activation of tumor-specific CD4+ T helper and cytotoxic 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. We hypothesize that because the vaccine cells do not express invariant chain (Ii), they preferentially present tumor-encoded peptides, rather than exogenously synthesized peptides, and thereby activate tumor-reactive T cells. 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 is present in many patients with cancer, and which inhibit both innate and adaptive immune system. The results described in Chapter 2 demonstrate that lung cancer MHC II vaccines activate tumor specific CD4+ T cells from the blood of healthy donors and lung cancer patients despite the presence of immune suppressive cells. Further, MHC II vaccines prime and boost CD4+ T cells that cross react with other subtypes of lung cancer cells but do not react with non-lung tumor cells or with normal lung fibroblast cells (Chapter 3).Various mechanisms of immune suppression have been attributed to MDSC, including arginine depletion by arginase production, iNOS production, however since MDSC is an emerging new field many more mechanisms are under their way. I have found a new mechanism through which MDSC also block T cell proliferation by sequestering cysteine, which is an essential amino acid for T cell (Chapter 4). T cells require cysteine because they lack the enzyme cystathionase which converts methionine to cysteine, and because they do not have an intact xc- transporter and therefore cannot import cystine and reduce it to cysteine. Therefore, T cells depend on macrophages and dendritic cells to export cysteine via their ASC neutral amino acid transporter. MDSC express the xc- transporter and import cystine; however, they do not express the ASC transporter and do not export cysteine. Since the import rate of cystine by MDSC is similar to that of macrophages and dendritic cells, but MDSC do not release cysteine, MDSC compete with macrophages and DC for the available extracellular cystine, but do not contribute to the extracellular pool of cysteine necessary for T cell proliferation. Therefore, in the presence of MDSC, T cells are deprived of the cysteine they need to proliferate and their activation is blocked. In summary, MHC II lung cancer vaccines may be used to treat immune suppressed advanced stage lung cancer patients. Furthermore, provision of stable form of cysteine along with MHC II lung cancer vaccine could further enhance the effectiveness of these vaccines