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4685 Pro-Inflammatory Monocytes As Key Effector Cells in Peripheral Circulatory Inflammatory Storms Driven By IFN-γ and IL-6 Pathways in Imcd

Program: Oral and Poster Abstracts
Session: 652. MGUS, Amyloidosis, and Other Non-Myeloma Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Xuejiao Yin1*, Yi Liu1*, Hongyan Tong, M.D.2* and Liangshun You, MD1*

1Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
2Hematology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

Objective: Dysfunctional cytokine-driven inflammatory storms in patients with idiopathic multicentric Castleman disease (iMCD) are a recurring issue affecting both symptoms and mortality, yet a thorough understanding of the involved immune cells remains incomplete. A comprehensive and detailed peripheral immune landscape is crucial for effectively treating iMCD.

Design: We employed single-cell RNA sequencing of 150936 cells from a cohort of 19 individuals, including 15 iMCD patients with mild or severe disease, as well as 4 healthy controls. For validation, we also enrolled a second cohort of 108 newly diagnosed iMCD patients with available IFN-γ data from 2015 to 2024.

Results: The activation and mobilization pervasive across all immune cells subtype during flares contribute to widespread systemic inflammatory storm in iMCD. Peripheral memory B C2 cells were the main source of plasma B and activated B cells in iMCD. Additionally, this cell subpopulation is where IL-6 mRNA is predominantly found in peripheral blood mononuclear cells (PBMCs). PADI/CCL/IL7R monocytes may be the primary effector cells in peripheral circulatory inflammatory storms. These cells exhibit the highest inflammatory scores, show the greatest activation of IL-6 signaling pathways, and overproduce VEGF-A, thereby being classified as pro-inflammatory monocytes. Furthermore, pro-inflammatory monocytes stimulated the overproduction of IL6 through promoting memory B C2 cell proliferation and transitions via BAFF signaling pathway, thus forming a vicious cycle that constantly stimulates the generation and expansion of inflammatory storms. In the cell-cell communication analysis, we identified IFN-II as a crucial signaling pathway, uniquely enriched in iMCD, with the highest relative strength index in both count and weight signaling patterns. Ligand-receptor analysis showed IFNG was mainly expressed in KLCRC2 NK, GZMK NK, NKT, and CD8TEX cells, whereas IFNGR1 and IFNGR2 were mainly expressed in pro-inflammatory monocytes. Besides, the level of IFNG expression was observed to correlate with iMCD severity. In the second iMCD cohort used for validation, IFN-γ levels were positively correlated with disease severity but negatively correlated with treatment response and progression-free survival (PFS).

Conclusion: This study provided an important resource for in-depth understanding the pathogenesis of iMCD and identify additional therapeutic strategies.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH