Expression of Immune Checkpoint Receptors in Multiple Myeloma Patients

Abstract

Abstract Multiple myeloma is a malignancy of plasma cells and the second most common hematologic cancer. High-dose chemotherapy plus autologous stem cell transplantation has been performed to achieve remission, but almost all the patients will finally relapse. Alternative therapeutic options are necessary for the multiple myeloma patients. Immune checkpoint inhibitors, such as anti-PD-1 have shown practice-changing therapeutic effectiveness for advanced non-small cell lung cancer, as well as Hodgkin’s lymphoma. To investigate T cell exhaustion in multiple myeloma patients, we assessed the expression of various immune checkpoint receptors, such as PD-1, Tim-3, LAG-3 and TIGIT, in the paired peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC), by multicolor flow cytometry. In BMMC, PD-1+, and PD-1+TIGIT+ were increased in CD8+ T cells, compared to the paired PBMC. Only a few patients showed Tim-3+ or LAG-3+ T cell population, and the most identified Tim-3+ or LAG-3+ T cell populations were observed in PD-1hiCD8+ T cells in the BMMC. There was significantly increased PD-1+, and PD-1+TIGIT+ expression in CD69+CCR7−CD8+ population compared to CD69− CCR7−CD8+ in BMMC. On direct ex vivo MHC multimer analysis of BMMC, tumor-associated-antigen specific CD8+ T cell showed increased PD-1+, TIGIT+, PD-1+TIGIT+ and CD69+ expression. PD-L1 was also expressed on malignant plasma cell, and the level of expression was correlated with the disease burden. Collectively, our data show that the immune checkpoint receptors-expressing T cells are enriched in bone marrow, where malignant plasma cells reside. Functional restoration of these T cells by immune checkpoint blockers will be investigated in further study.