Work

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

Year: 2025

Type: article

Abstract: Background: Multiple myeloma (MM), a plasma cell malignancy, is incurable and 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 patients with MM correlate with inferior outcome. 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. We investigated the interaction between CD14+ monocytes and T-lymphocytes, as well as the corresponding downstream signaling mechanism through in vitro and in vivo experiments. Results: The alterations in MHC Ⅱ signaling of related to outgoing interaction was 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 an 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. This study lays the foundation for understanding the immuno-suppressive environment in MM, improving the efficacy of immunotherapy based on T-lymphocytes, and developing new therapeutic targets.

Source: Journal of Translational Medicine

DOI: 10.1186/s12967-025-06516-0