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Multi-omics reveal immune microenvironment alterations in multiple myeloma and its precursor stages

Yan ChengMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAFumou SunMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USADaisy AlapatDepartment of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAVisanu WanchaiMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USADavid E. MeryMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAEric R. SiegelDepartment of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAHongwei XuMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USASadie JohnsonMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAWancheng GuoMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAClyde BaileyMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USACody AshbyDepartment of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAMichael BauerDepartment of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USASamer Al HadidiMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USACarolina SchinkeMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USASharmilan ThanendrarajanMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAMaurizio ZangariMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAFrits van RheeMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAGuido TricotMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USAJohn D. ShaughnessyMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. [email protected]Fenghuang ZhanMyeloma Center, Winthrop P. Rockefeller Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. [email protected]

2024en

ABI

Annotatsiya

Abstract Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16 + monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8 + T cells shift from a GZMK + to a GZMB + cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB + CD8 + T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8 + T cell versatility in precursor stages may prevent MM progression.

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DOI: 10.1038/s41408-024-01172-x

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