Dysregulation of Antigen Presenting Cell Function in Cancer

Division Of Basic Sciences - Nci

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Abstract

We have published a study highlighting a novel process of immune evasion employed by tumor cells. DCs present in the tumor draining lymph nodes (tdLN) of tumor-bearing mice fail to stimulate antigen-specific CD4 T cells both in vivo and in vitro whereas stimulation of antigen-specific CD8 T cells by these DCs was not. We found that although total expression of MHC-II on tdLN DCs was essentially normal, MHC-II molecules on these cells were unable to efficiently bind antigenic peptides. We found that MHC-II on tdLN DCs contain large amounts of a small endogenous peptide, termed CLIP, in the MHC-II peptide binding groove that prevents antigenic peptide binding to MHC-II. Enhanced MHC-II-CLIP expression was a consequence of diminished expression of the peptide editor HLA-DM and enhanced activity of the CLIP-generating proteinase cathepsin S specifically in tdLN DCs. These data reveal a novel mechanism of immune evasion induced by tumors that limits CD4 T cell recognition of MHC-II on tdLN DCs.