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Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

ABSTRACT: Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124310 | GEO | 2020/04/28

REPOSITORIES: GEO

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Project description: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. CIBERSORT analysis revealed proportions of 27 cell types, including 10 innate immune cells (monocytes, M0/M1/M2 macrophages, resting/activated dendritic cells, resting/activated mast cells, eosinophils, and neutrophils), 7 T cell subsets (CD8+ T cells, naive CD4+ T cells, resting/activated memory CD4+ T cells, follicular helper T cells, regulatory T cells, and gamma delta T cells), resting/activated NK cells, naive B cells, memory B cells, plasma cells, myeloma plasma cells, memory plasma cells, osteoblasts, osteoclasts and adipocytes. We removed plasma cells (PC) from the 100% total cell proportions to avoid bias resulting from different tumor burdens. We found that the proportions of neutrophils, mast cells, and monocytes account for the majority of innate immune cells and were decreased in NDMM and its precursor stages when compared with NBM. We noticed a significant abundance of M2 macrophages in NDMM, but not in the precursor stages. The proportion of CD8+ T cells was increased at the SMM and MM stages, and the proportion of activated memory CD4+ T cells continued to decrease from NBM to MGUS, SMM, and MM. We performed correlation analysis of immune cell proportions with the time of progression of MGUS and SMM patients. We observed neutrophil proportions were negatively correlated with the time to progression in SMM patients, indicating more neutrophils predict inferior outcomes for SMM patients. However, in NDMM patients, we observed that the neutrophil percentage was decreased in patients with high-risk status based on the 70-gene Prognostic Risk Score (GEP-70) or at stage III of International Staging System (ISS), and patients with high proportions of neutrophils had a significantly superior overall survival (OS) and event-free survival (EFS). For T cell populations, we observed that the proportions of CD8+ T cells were negatively correlated with the time of progression in SMM patients and the γδ T cells were positively correlated. We observed the proportions of γδ T cells were also positively correlated with the time of progression in MGUS patients. Consistent with the time-to-progression data, high-risk SMM patients showed higher proportions of CD8+ T cells and lower proportions of naïve CD4+ T cells and γδ T cells.

Project description:Smoldering myeloma (SMM) is a pre-malignant monoclonal gammopathy with a 10% annual risk to progress to active multiple myeloma (MM). SMM diagnostic criteria, as well of those of others monoclonal gammopathies, have been updated by the International Myeloma Working Group (IMWG) in 2014. In particular, the previously defined “ultra high-risk” SMM (characterized by the presence of specific biomarkers associated with a ≥ 80% risk of progression to symptomatic MM within 2 years) has been included among patients with active MM. SMM is biologically heterogeneous, including a subset of patients with biological pre-malignancy and a subset with biological malignancy who have not yet developed organ damage, defined as onset of the classical CRAB criteria or Myeloma Defining Events (MDE). Thus, SMM encompassed patients with a very low rate of progression to symptomatic MM, similar to patients with monoclonal gammopathy of uncertain significance (MGUS), as well as patients who acquired organ damage and progress to active MM within the first year from diagnosis. The molecular mechanisms involved in the SMM to MM progression are still far to be fully understood. Genomic studies indicate that the genetic alterations that characterize MM patients are already present in SMM ones, who present similar mutational and copy number alteration load. However, few data are available on the transcriptional profiles of SMM patients in relationship to the progression to active MM, overall indicating minimal differential expression either in coding or non-coding RNA fraction. To date, robust data are still lacking which describe the transcriptional profiles of plasma cells (PCs) from paired samples obtained at the time of SMM and at MM onset. Herein, we compared the transcriptome of purified CD138+ PCs from paired samples of SMM patients progressed to active MM (P-SMM), aimed at describing any possible common transcriptional discrepancy that may help to understand the intra-patient disease evolution; at the same time, we investigated the transcriptional differences between P-SMM and a subset of non-progressed SMM (NP-SMM) at a minimum of 36 months.

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Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

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