CD34+ and CD34- MM cells show different immune-checkpoint molecule expression profiles: high expression of CD112 and CD137 ligand on CD34+ MM cells.

Despite the introduction of new drugs, multiple myeloma (MM) still remains incurable. We previously reported that CD34⁺ MM cells, which are clonogenic and self-renewing, are therapy-resistant and persist as a major component of minimal residual disease, expanding during relapse. To investigate the effects of immunotherapies such as immune-checkpoint inhibitors, CAR-T therapy, and bispecific antibodies on CD34⁺ MM cells, we analyzed immune profiles of both MM cells and T cells from MM patients using microarrays and flow cytometry. Ingenuity pathway analysis revealed 14 out of 289 canonical pathways were more active in CD34⁺ MM cells compared to CD34^- cells, many of which were involved in inflammation and immune responses. Notably, PD-1 signaling-related genes were highly expressed in CD34⁺ MM cells. Among 10 immune-checkpoint molecules, CD34⁺ cells more frequently expressed CD112, CD137L, CD270, CD275, and GAL9 than CD34^- cells in both newly diagnosed and relapsed/resistant patients. In addition, CD4⁺ and CD8⁺ T cells more frequently expressed TIGIT and CD137, suggesting that CD112/TIGIT and CD137L/CD137 interactions may suppress T-cell activity against CD34⁺ MM cells. Furthermore, our finding of higher FcRH5 expression on CD34⁺ MM cells is encouraging for future research into the efficacy of FcRH5-targeted therapy in MM.