BALB/c Invariant Chain Mutant Mice Display Relatively Efficient Maturation of CD4+ T Cells in the Periphery and Secondary Proliferative Responses Elicited upon Peptide Challenge

We are developing vaccines that activate tumor-specific CD4+ T cells. The cell-based vaccines consist of MHC class I+ tumor cells that are genetically modified to express syngeneic MHC class II and costimulatory molecules. Previous studies demonstrated that treatment of mice with established tumors with these vaccines resulted in regression of solid tumors, reduction of metastatic disease, and increased survival time. Optimal vaccines will prime naïve T cells and activate T cells to tumor peptides derived from diverse subcellular compartments, since potential tumor antigens may reside in unique cellular locales. To determine if the MHC class II/costimulatory molecule vaccines fulfill these conditions, the vaccines have been tested for their ability to activate antigen-specific, naïve, transgenic CD4+ T lymphocytes. MHC class II(+)CD80+ vaccine cells were transfected with hen eggwhite lysozyme targeted to the cytosol, nuclei, mitochondria, or endoplasmic reticulum, and used as antigen-presenting cells to activate I-Ak-restricted, lysozyme-specific CD4+ 3A9 transgenic T cells. Regardless of the cellular location of lysozyme, the vaccines stimulated release of high levels of IFN-gamma and IL-2. If the vaccines coexpressed the MHC class II accessory molecule invariant chain, then IFN-gamma and IL-2 release was significantly reduced. These studies demonstrate that in the absence of invariant chain the MHC class II and CD80 tumor cell vaccines (1) function as antigen-presenting cells to activate naïve, tumor-specific CD4+ cells to endogenously synthesized tumor antigens; (2) polarize the activated CD4+ T cells toward a type 1 response; and (3) present epitopes derived from varied subcellular locales.

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Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells

Bosch

Iheagwara

Reid

et al. 2009

Cancer Immunol Immunother

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We are exploring cell-based vaccines as a treatment for the 50% of patients with large primary uveal melanomas who develop lethal metastatic disease. MHC II uveal melanoma vaccines are MHC class I+ uveal melanoma cells transduced with CD80 genes and MHC II genes syngeneic to the recipient. Previous studies demonstrated that the vaccines activate tumor-specific CD4+ T cells from patients with metastatic uveal melanoma. We have hypothesized that vaccine potency is due to the absence of the MHC II-associated invariant chain (Ii). In the absence of Ii, newly synthesized MHC II molecules traffic intracellularly via a non-traditional pathway where they encounter and bind novel tumor peptides. Using confocal microscopy, we now confirm this hypothesis and demonstrate that MHC II molecules are present in both the endosomal and secretory pathways in vaccine cells. We also demonstrate that uveal melanoma MHC II vaccines activate uveal melanoma-specific, cytolytic CD8+ T cells that do not lyse normal fibroblasts or other tumor cells. Surprisingly, the CD8+ T cells are cytolytic for HLA-A syngeneic and MHC I-mismatched uveal melanomas. Collectively, these studies demonstrate that MHC II uveal melanoma vaccines are potent activators of tumor-specific CD4+ and CD8+ T cells and suggest that the non-conventional intracellular trafficking pattern of MHC II may contribute to their enhanced immunogenicity. Since MHC I compatibility is unnecessary for the activation of cytolytic CD8+ T cells, the vaccines could be used in uveal melanoma patients without regard to MHC I genotype.

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BALB/c Invariant Chain Mutant Mice Display Relatively Efficient Maturation of CD4+ T Cells in the Periphery and Secondary Proliferative Responses Elicited upon Peptide Challenge

Cited by 31 publications

References 108 publications

Scope of the Thesis

Scope of the Thesis

MHC class II and CD80 tumor cell?based vaccines are potent activators of type 1 CD4 + T lymphocytes provided they do not coexpress invariant chain

Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells

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