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

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CD14 Multiple myeloma Expression (computer science) Cancer research Immunology Biology Internal medicine Medicine Computer science Immune system Programming language

Fengping Peng , Zhaoyun Liu , Fengjuan Jiang , Nianbin Li , Hao Wang , Nanhao Meng , Hui Liu , Kai Ding , Rong Fu ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.21203/rs.3.rs-6254013/v1 · OA: W4410299014

<title>Abstract</title> <bold>Background:</bold> 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. <bold>Methods:</bold> 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 <italic>in vitro </italic>and <italic>in vivo</italic> experiments. <bold>Results:</bold> 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 (<italic>ULK2</italic>) 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 <italic>ULK2</italic> suppressed T-lymphocytes and promoted tumor growth. <bold>Conclusion:</bold> 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.