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 Avigan; Shaji K Kumar; Sacha Gnjatic; Li Ding; Manoj Bhasin

doi:10.1038/s41525-022-00340-x

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

NPJ Genom Med. 2023 Jan 26;8(1):3. doi: 10.1038/s41525-022-00340-x.

Authors

William Pilcher^{1

2}, Beena E Thomas^{1

3}, Swati S Bhasin^{1

3}, Reyka G Jayasinghe⁴, Lijun Yao⁴, Edgar Gonzalez-Kozlova^{5

6}, Surendra Dasari⁷, Seunghee Kim-Schulze^{5

8}, Adeeb Rahman^{5

6}, Jonathan Patton¹, Mark Fiala⁴, Giulia Cheloni⁹, Taxiarchis Kourelis¹⁰, Madhav V Dhodapkar^{11

12}, Ravi Vij¹³, Shaadi Mehr¹⁴, Mark Hamilton¹⁴, Hearn Jay Cho^{5

14}, Daniel Auclair¹⁴, David E Avigan^#⁹, Shaji K Kumar^#¹⁰, Sacha Gnjatic^#^{5

8}, Li Ding^#⁴, Manoj Bhasin^#^{15

16

17

18

19}

Affiliations

¹ Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
² Coulter Department of Biomedical Engineering, Emory University, Atlanta, GA, USA.
³ Department of Pediatrics, Emory School of Medicine, Atlanta, GA, USA.
⁴ Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
⁵ Human Immune Monitoring Center, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Division of Biomedical Statistics & Informatics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
¹⁰ Mayo Clinic Rochester, Division of Hematology, Rochester, MN, USA.
¹¹ Department of Hematology/Medical Oncology Emory University School of Medicine, Atlanta, GA, USA.
¹² Winship Cancer Institute, Emory University, Atlanta, GA, USA.
¹³ Washington University School of Medicine, St Louis, MO, USA.
¹⁴ Multiple Myeloma Research Foundation (MMRF), Norwalk, CT, USA.
¹⁵ Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA. manoj.bhasin@emory.edu.
¹⁶ Coulter Department of Biomedical Engineering, Emory University, Atlanta, GA, USA. manoj.bhasin@emory.edu.
¹⁷ Department of Pediatrics, Emory School of Medicine, Atlanta, GA, USA. manoj.bhasin@emory.edu.
¹⁸ Winship Cancer Institute, Emory University, Atlanta, GA, USA. manoj.bhasin@emory.edu.
¹⁹ Department of Biomedical Informatics, Emory School of Medicine, Atlanta, GA, USA. manoj.bhasin@emory.edu.

^# Contributed equally.

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.

Abstract

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