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 V(L), 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.