Journal Article

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

Fronick, Catrina C., Vij, Ravi, King, Justin, Oh, Stephen T., Wang, Julia Tianjiao, Kohnen, Daniel R., Wyczalkowski, Matthew A., Yao, Lijun, Goldsmith, Scott R., Liu, Ruiyang, Cao, Song, DiPersio, John F., Ding, Li, McMichael, Joshua F., Fiala, Mark A., Fowles, Jared S., Sun, Hua, Rettig, Michael P., Wendl, Michael C., O’Neal, Julie, Weerasinghe, Amila, Storrs, Erik P., Gao, Qingsong, Foltz, Steven M., Jayasinghe, Reyka G., Sethuraman, Sunantha, Ley, Timothy J., Fulton, Robert S., Yoon, Christopher J.

2021

Overview

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. Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/39 / 45/23 / 45/91 / 631/67/1990/804 / 631/67/2329 / 631/67/327 / 631/67/69 / Aged / B-Lymphocytes - cytology / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Cell Lineage / Cell proliferation / Clonal Evolution - genetics / Coevolution / Cohort Studies / Diagnosis / Disease Progression / Evolution / Female / Gene Expression Regulation, Neoplastic - genetics / Gene Expression Regulation, Neoplastic - immunology / Gene mapping / Gene sequencing / Haplotypes / Humanities and Social Sciences / Humans / Immune system / Interleukin 1 / Interleukin 6 / Interleukin-1beta - blood / Interleukin-6 - blood / Lymphocytes B / Male / Mass Spectrometry / Microenvironments / Middle Aged / multidisciplinary / Multigene Family / Multiple myeloma / Multiple Myeloma - blood / Multiple Myeloma - genetics / Multiple Myeloma - immunology / Multiple Myeloma - pathology / Mutation / Neoplasm Recurrence, Local - blood / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - immunology / Plasma / Plasma cells / Proto-Oncogene Proteins c-fos - blood / Proto-Oncogene Proteins c-jun - blood / Ribonucleic acid / RNA / RNA-Seq / Science / Science (multidisciplinary) / Signal Transduction - genetics / Signal Transduction - immunology / Single-Cell Analysis / Subpopulations / Transcription factors / Tumor Microenvironment - immunology / Tumors / Whole genome sequencing