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.
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.
Bosch
Jacobus J
JJ
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA.
Iheagwara
Uzoma K
UK
Reid
Sarah
S
Srivastava
Minu K
MK
Wolf
Julie
J
Lotem
Michal
M
Ksander
Bruce R
BR
Ostrand-Rosenberg
Suzanne
S
D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D055571:Secretory Pathway; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014604:Uveal Neoplasms / Q000276:immunology* / Q000378:metabolism
D019496:Cancer Vaccines; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II