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

William Pilcher, Beena E. Thomas, Swati S. Bhasin, Reyka G. Jayasinghe, Lijun Yao, Edgar Gonzalez-Kozlova, Surendra Dasari, Seunghee Kim-Schulze, Adeeb Rahman, Jonathan Patton, Mark Fiala, Giulia Cheloni, Taxiarchis Kourelis, Madhav V. Dhodapkar, Ravi Vij, Shaadi Mehr, Mark Hamilton, Hearn Jay Cho, Daniel Auclair, David E. AviganShaji K. Kumar, Sacha Gnjatic, Li Ding, Manoj Bhasin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Article number3
Journalnpj Genomic Medicine
Volume8
Issue number1
DOIs
StatePublished - Dec 2023

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