Cross center single-cell RNA sequencing study of the immune microenvironment in rapid progressing multiple myeloma

• Type of Material: Article
• Authors: William Pilcher, Aflac Cancer and Blood Disorders Center; Beena E Thomas, Aflac Cancer and Blood Disorders Center; Swati Bhasin, Emory University; Reyka G Jayasinghe, Washington University; Lijun Yao, Washington University; Edgar Gonzalez-Kozlova, Icahn School of Medicine at Mt. Sinai; Surendra Dasari, Mayo Clinic; Seunghee Kim-Schulze, Icahn School of Medicine at Mt. Sinai; Adeeb Rahman, Icahn School of Medicine at Mt. Sinai; Jonathan Patton, Aflac Cancer and Blood Disorders Center, Atlanta; Mark Fiala, Washington University; Giulia Cheloni, Harvard Medical School; Taxiarchis Kourelis, Mayo Clinic Rochester; Madhav Dhodapkar, Emory University; Ravi Vij, Washington Univ; Shaadi Mehr, Multiple Myeloma Research Foundation (MMRF); Mark Hamilton, Multiple Myeloma Research Foundation (MMRF); Hearn Jay Cho, Icahn School of Medicine at Mt. Sinai; Daniel Auclair, Multiple Myeloma Research Foundation (MMRF); David E Avigan, Harvard Medical School; Shaji K Kumar, Mayo Clinic Rochester; Sacha Gnjatic, Icahn School of Medicine at Mt. Sinai; Li Ding, Washington Univ; Manoj Bhasin, Emory University
• Language: English
• Date: 2023-01-26
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41525-022-00340-x
• Title of Journal or Parent Work: NPJ GENOMIC MEDICINE
• Volume: 8
• Issue: 1
• Start Page: 3
• End Page: 3
• Keywords: EXPRESSION; ATACICEPT; PATHWAY; ADHESION; GROWTH; Life Sciences & Biomedicine; BONE-MARROW MICROENVIRONMENT; Science & Technology; BAFF; Genetics & Heredity; PLASMA-CELLS
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM’s progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138- BM samples collected at the time of disease diagnosis from 18 patients with either rapid progressing (progression-free survival (PFS) < 18 months) or non-progressing (PFS > 4 years) disease. Comparative analysis of data from three centers demonstrated similar transcriptome profiles and cell type distributions, indicating subtle technical variation in scRNA-seq, opening avenues for an expanded multicenter trial. Rapid progressors depicted significantly higher enrichment of GZMK+ and TIGIT+ exhausted CD8+ T-cells (P = 0.022) along with decreased expression of cytolytic markers (PRF1, GZMB, GNLY). We also observed a significantly higher enrichment of M2 tolerogenic macrophages in rapid progressors and activation of pro-proliferative signaling pathways, such as BAFF, CCL, and IL16. On the other hand, non-progressive patients depicted higher enrichment for immature B Cells (i.e., Pre/Pro B cells), with elevated expression for markers of B cell development (IGLL1, SOX4, DNTT). This multi-center study identifies the enrichment of various pro-tumorigenic cell populations and pathways in those with rapid progressing disease and further validates the robustness of scRNA-seq data generated at different study centers.