Targeting human B-cell malignancies through Ig light chain-specific cytotoxic T lymphocytes

Purpose: The variable regions of Ig (idiotype, Id) expressed by malignant B cells can be used as tumor-specific antigens that induce humoral and cellular immunity. However, epitopes derived from Id that stimulate human CD8 ⁺ T-cell immunity are incompletely characterized. Experimental Design: The clonal Ig V _L of human myeloma cell line U266 and five primary B-cell tumors were sequenced, and peptides corresponding to the Ig V _L region were tested for their ability to stimulate CTLs from 10 HLA-A*0201-positive normal donors. The CTLs thus generated were tested against peptide-pulsed T2 cells and autologous tumor cells. Results: Fourteen peptides derived from Ig light chain (V _L) of U266 and primary B-cell tumors were used to generate 68 CTLs lines that specifically produced IFN-γ when cocultured with peptide-pulsed T2 cells. These CTLs lysed peptide-pulsed T2 cell as well as U266 or autologous tumor targets in an HLA class I-dependent manner. Sequence analysis revealed shared V _L T-cell epitopes in U266 and primary B-cell tumors, not previously reported within Ig heavy chain (V _H) sequences. Conclusion: This study thus identifies novel immunogenic CTLs epitopes from Id VL, suggests that they are naturally presented on the surface of B-cell malignancies, and supports their inclusion in next-generation Id vaccines. The ability to prime T cells derived from normal HLA-matched donors, rather than patients, may also have direct application to current strategies, designed to generate allogeneic tumor-specific T cells for adoptive transfer.