T-lymphocytes suppression by CD14+ monocytes with high expression of ULK2 in patients with multiple myeloma

BACKGROUND: Multiple myeloma (MM), a plasma cell malignancy, remains incurable and is highly prone to relapse. Immunosuppressive cells in the bone marrow environment inhibit endogenous T-lymphocytes activity and reduce the efficacy immunotherapies. Abnormal bone marrow monocytes in MM have been associated with inferior outcomes. This study explored the mechanism of T-lymphocytes suppression by bone marrow CD14(+) monocytes in MM. METHODS: Single-cell RNA sequence data (GSE124310) derived from MM samples were analyzed. CD14(+) monocytes from the bone marrow of patients with newly-diagnosed MM were detected, and RNA sequencing was performed. Interactions between CD14(+) monocytes and T-lymphocytes, as along with the corresponding downstream signaling mechanism, were assessed through in vitro and in vivo experiments. RESULTS: The alterations in MHC II signaling related to outgoing interaction were decreased in CD14 + monocytes from patients with MM. Abnormal numbers, defective antigen presentation, and downregulated surface co-stimulatory molecules in bone marrow CD14(+) monocytes were also observed. RNA sequencing identified upregulated expression of Unc-51 like autophagy activating kinase 2 (ULK2) in these monocytes, a protein involved in the antigen processing and presentation pathway. CD14(+) monocytes from patients with NDMM suppressed T-lymphocyte activity, and treatment of CD14(+) monocytes with a ULK1/ULK2 inhibitor alleviated this suppression. MM xenograft model showed that CD14(+) monocytes high-expressing ULK2 suppressed T-lymphocytes and promoted tumor growth. CONCLUSION: We demonstrated that CD14(+) monocytes from MM can disrupt the delivery of antigenic peptides through the antigen processing and presentation pathway. This disruption affects T-lymphocytes activity and attenuates their ability to kill malignant cells and secrete cytokines. These findings lay the foundation for understanding the immuno-suppressive environment in MM, improving the efficacy of immunotherapy based on T-lymphocytes, and developing new therapeutic targets.