Lymphoid malignancies such as lymphoma and leukemia often compromise host defense and have evolved mechanisms to evade immune surveillance. Burkitt lymphoma (BL) is a poorly immunogenic, highly malignant B-cell tumor characterized by chromosomal translocations that constitutively activate the c-myc oncogene. Effective tumor immune responses usually involve the stimulation and maintenance of tumor specific CD8+ HLA class I restricted T effector cells and tumor-specific CD4+ class II restricted T cells. Several groups have shown that BL can not present antigens (Ags) by class I molecules which contribute to their escaping immune recognition from tumor-specific CD8+ T cells. Recently, studies have also shown that HLA class II-restricted CD4+ cytotoxic T cells (CTL) could be generated against BL and as well as non-Hodgkins follicular lymphoma (FL). These studies support the feasibility of using sufficient tumor specific CD4+ T cells to eliminate B-cell tumors. Most B-cell tumors, including BL, express class II molecules, could provide their own MHC class II Ag presentation and be targets for CD4+ T cells. As BL are very poorly immunogenic, we hypothesize that BL and other B-cell lymphomas may also have a defect in stimulation of tumor-specific CD4+ T cells. Our data suggest that CD4+ T cells are unable to recognize Ag in association with HLA class II on BL/FL cells whereas, Epstein Barr Virus (EBV) infected B-cell lymphoblasts (B-LCL) efficiently process and present Ags to T cells in the context of class II molecules. The overall goal of this project is to elucidate the defect(s) in BL/FL responsible for this loss of Ag presentation by HLA class II and to assess whether these identified defect(s) are a global trait of B-cell lymphomas. We will determine the mechanisms for poor class II restricted HLA Ag presentation by BL, FL and other B-cell lymphomas using the following three specific aims: (1) Determine the defective step(s) in Burkitt lymphoma and other B-cell lymphomas that suppress the stimulation of Ag-specific, CD4+ HLA-class II-restricted T cells, (2) Determine mechanisms induced at pH 5.5 that restore the ability of Burkitt lymphoma to stimulate Ag-specific, CD4+ HLA-class II-restricted T cells, and (3) Identify and clone the inhibitory factors shed by Burkitt lymphoma at pH 5.5 that suppress HLA class II-restricted Ag presentation. Cellular, biochemical, molecular, proteomics and functional approaches will be employed to test these aims. These studies will elucidate novel mechanism(s) for restoring Ag presentation to BL cells and for suppressing B-LCL and DC Ag-class II presentation. The elucidated mechanisms will likely spur development of novel strategies to restore CD4+ T cell recognition and clearance of BL and other B-cell lymphomas.
Our studies suggest that there is a defect(s) in HLA class II-mediated immune recognition of B-cell lymphomas, and it likely contributes to tumor cell escape from host defenses. This study will define the defect(s) in B-cell lymphomas responsible for this loss of antigen presentation and CD4+ T cell recognition via HLA class II molecules. The elucidated findings will likely spur development of novel strategies to restore CD4+ T cell recognition and clearance of BL and other B-cell lymphomas.
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