Disruption of HLA Class II-Mediated Immune Recognition of B-Cell Lymphomas

Summary

Principal Investigator: Azizul Haque
Abstract: 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. PUBLIC HEALTH RELEVANCE: 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.
Funding Period: 2009-03-01 - 2014-12-31
more information: NIH RePORT

Top Publications

  1. pmc Regulation of Th1/Th17 cytokines and IDO gene expression by inhibition of calpain in PBMCs from MS patients
    Amena W Smith
    Department of Neurosciences, Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas St, Charleston, SC 29425, USA
    J Neuroimmunol 232:179-85. 2011
  2. ncbi Molecular alterations in glioblastoma: potential targets for immunotherapy
    Azizul Haque
    Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
    Prog Mol Biol Transl Sci 98:187-234. 2011
  3. ncbi Mechanisms regulating enhanced human leukocyte antigen class II-mediated CD4 + T cell recognition of human B-cell lymphoma by resveratrol
    Faisal F Y Radwan
    Department of Microbiology and Immunology, Hollings Cancer Center and Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Leuk Lymphoma 53:305-14. 2012
  4. pmc Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1
    Dan Zhao
    Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
    Cell Immunol 271:392-400. 2011
  5. pmc HLA class II defects in Burkitt lymphoma: bryostatin-1-induced 17 kDa protein restores CD4+ T-cell recognition
    Azim Hossain
    Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
    Clin Dev Immunol 2011:780839. 2011
  6. pmc A possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma
    Azim Hossain
    Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, BSB 201, Charleston, SC 29425, USA
    Apoptosis 17:1066-78. 2012

Detail Information

Publications9

  1. pmc Regulation of Th1/Th17 cytokines and IDO gene expression by inhibition of calpain in PBMCs from MS patients
    Amena W Smith
    Department of Neurosciences, Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas St, Charleston, SC 29425, USA
    J Neuroimmunol 232:179-85. 2011
    ..These results suggest that calpain inhibition may attenuate MS pathology and augment the efficacy of standard immunomodulatory agents used to treat this disease...
  2. ncbi Molecular alterations in glioblastoma: potential targets for immunotherapy
    Azizul Haque
    Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
    Prog Mol Biol Transl Sci 98:187-234. 2011
    ..This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression, and the future design of chemoimmunotherapeutics against glioblastoma...
  3. ncbi Mechanisms regulating enhanced human leukocyte antigen class II-mediated CD4 + T cell recognition of human B-cell lymphoma by resveratrol
    Faisal F Y Radwan
    Department of Microbiology and Immunology, Hollings Cancer Center and Children s Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
    Leuk Lymphoma 53:305-14. 2012
    ..These findings suggest that HLA class II-mediated immune recognition of malignant B-cells can be improved by Resv treatment, thus encouraging its potential use in chemoimmunotherapy of B-cell lymphoma...
  4. pmc Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1
    Dan Zhao
    Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
    Cell Immunol 271:392-400. 2011
    ..These data suggest that bryostatin-1 could be used as a chemo-immunotherapeutic agent for reducing tumorigenic potential of melanoma cells while enhancing CD4+ T cell recognition to prevent tumor recurrence...
  5. pmc HLA class II defects in Burkitt lymphoma: bryostatin-1-induced 17 kDa protein restores CD4+ T-cell recognition
    Azim Hossain
    Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
    Clin Dev Immunol 2011:780839. 2011
    ..These results demonstrate the presence of a specific defect in HLA class II-mediated Ag presentation in BL and reveal that treatment with bryostatin-1 could lead to enhanced immunogenicity...
  6. pmc A possible cross-talk between autophagy and apoptosis in generating an immune response in melanoma
    Azim Hossain
    Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, BSB 201, Charleston, SC 29425, USA
    Apoptosis 17:1066-78. 2012
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