Cyclin D1 as a universally expressed mantle cell lymphoma-associated tumor antigen for immunotherapy

Mantle cell lymphoma (MCL) accounts for 5-10% of all non-Hodgkin lymphomas and has the worst prognosis among all lymphomas. The hallmark of MCL is a t(11;14) translocation that results in overexpression of cyclin D1 by tumor cells of virtually all patients. In this study, we examined whether cyclin D1 could be an effective tumor-associated antigen for immunotherapy. We identified cyclin D1 peptides for HLA-A*0201 and generated peptide-specific CD8⁺ T-cell lines from HLA-A*0201⁺ blood donors and MCL patients. These cell lines proliferated in response to cyclin D1 peptide-pulsed stimulatory cells. Moreover, the T cells efficiently lysed peptide-pulsed but not unpulsed T2 cells and autologous dendritic cells; cyclin D1⁺ and HLA-A*0201⁺ human MCL lines MINO, SP53, Jeko-1 and Granta 519; and more importantly, HLA-A*0201⁺ primary lymphoma cells from MCL patients. No killing was observed with HLA-A*0201^- primary lymphoma cells or HLA-A*0201⁺ normal blood cells, including B cells. These results indicate that these T cells are potent cytotoxic T cells and recognize cyclin D1 peptides naturally presented by patient lymphoma cells in the context of HLA-A*0201 molecules. Taken together, our work identifies cyclin D1 as a potentially important antigen for immunotherapy of MCL.