Co-evolution of tumor and immune cells during progression of multiple myeloma

Abstract

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect “B cell-featured” plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.

Metabolic Disorders in Multiple Myeloma

“…Since immune cells share the same metabolic requirements with myeloma cells, metabolic competition is created. During the disease course from asymptomatic to symptomatic and relapsing myeloma, the immune microenvironment is highly dynamic and changes in the immune signatures also result in changes in the metabolic profile [ 62 ]. Cancer cells, through hypoxia and lactate increase, have better access to nutrients, which promotes tumor survival and inhibits immune surveillance [ 63 ].…”

A Novel Model of Tumor-Infiltrating B Lymphocyte Specific RNA-Binding Protein-Related Genes With Potential Prognostic Value and Therapeutic Targets in Multiple Myeloma

“…We found that there were significant differences in immune cell infiltration, immune-related functions, immune-related pathways and the expression of immune checkpoint genes between the two groups. Several single-cell transcriptional studies have revealed that transcriptional programs are associated with aggressive myeloma progression and immune evasion (Ryu et al, 2020;Liu et al, 2021). According to the above findings, we present the hypotheses that the prognostic characteristic genes are highly associated with different immune microenvironments in the two groups.…”

Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma

“…As far as the relationship between immune response, inflammation, and mutational status, MM subjects with the same genetic alterations are inclined to have both plasma cells and immune cells clustered together [140].…”