Immunosuppressive Effects of Multiple Myeloma‐Derived Extracellular Vesicles Through T Cell Exhaustion

Extracellular vehicles (EVs) are reported to be involved in several processes relating to tumor progression, including angiogenesis, osteolysis, and drug resistance in multiple myeloma (MM). However, the role of EVs in the immune-suppressive milieu of MM is poorly understood. Here, we investigated the effects of MM-derived EVs on T cells, focusing on markers of T cell exhaustion. Using activated peripheral blood mononuclear cells from healthy donors, we observed immunosuppressive effects such as upregulated expression of immune checkpoint markers on CD8+ T cells treated with MM-derived EVs. Proteomic analysis identified several proteins, such as IL-8, SLC1A5, PIN2, and FSP1, associated with regulation of T cell exhaustion and chronic inflammation. Surprisingly, sphingosine kinase 1 (SPHK1) was enriched in MM cell line-derived EVs, implicating SPHK1/S1P signaling in the immunosuppressive effect of MM EVs. Thus, MM-derived EVs may promote T cell exhaustion via upregulating the expression of immune checkpoint markers and thereby contribute to the formation of the immune-suppressive milieu of MM, resulting in impaired T cell activity.