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.