Targeting B-cell malignancies through human B-cell receptor specific CD4+ T cells

ABSTRACTThe B-cell receptor(BCR) expressed by a clonal B cell tumor is a tumor specific antigen( idiotype). However, the T-cell epitopeswithin human BCRs which stimulate protective immunity still lack detailed characterization. In this study, we identified 17 BCR peptide-specific CD4+ T-cell epitopesderived from BCR heavy and light chain variable region sequences. Detailed analysis revealed these CD4+ T-cell epitopesstimulated normal donors' and patients' Th1 CD4+ T cells to directly recognize the autologous tumors by secretion of IFNγ, indicating the epitopesare processed and presented by tumor cells. One BCR peptide-specific CD4+ T cell line was also cytotoxic and lysed autologous tumor cellsthrough the perforinpathway. Sequence analysis of the epitopesrevealed that 10 were shared by multiple primary patients' tumors, and 16 had the capacity to bind to more than one HLA DRB1allele. T cells stimulated by shared epitopesrecognized primary tumors expressing the same sequences on multiple HLA DRB1...