Single‐cell atlas of the immune microenvironment reveals macrophage reprogramming and the potential dual macrophage‐targeted strategy in multiple myeloma

Abstract

Summary The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM). This study aimed to present an atlas of MM‐TME in disease progression and explore TME‐directed therapeutic strategies. We performed single‐cell RNA sequencing (scRNAseq) in samples from different disease stages. We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments. We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8+ T cells and reprogramming of macrophages (MPs). The reprogrammed tumour‐associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores. We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand–receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA‐CD47 pathway suppressing phagocytosis and the CD74–MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes. We designed a dual‐MP‐targeted strategy by combining an anti‐CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo. We drafted alterations in MM‐TME during disease progression and unravelled TAM's reprogramming. The dual MP‐targeted approach blocking both CD47 and MIF showed potent antitumour effects.

Good Cop, Bad Cop: Profiling the Immune Landscape in Multiple Myeloma

“…Additionally, major histocompatibility complex (MHC)-class II dysregulation in CD14+ monocytes leads to T-cell suppression in vitro [281]. A compromised tumor microenvironment was also demonstrated in a study combining SCTS with validation using bulk RNA sequencing (RNAseq), flow cytometry, and functional experiments [285]. Results showed enrichment of exhausted NK cells and CD8+ T cells, macrophage reprogramming to a mixed M1-M2 phenotype, and two TAM clusters present only in the MM stage with increased M2 scores.…”

Mesenchymal stem cells-macrophages crosstalk and myeloid malignancy

“…High levels of CXCL13 can promote the proliferation of MM cells and the polarization of M2 macrophages and are potentially associated with extramedullary involvement in MM. Li et al performed single-cell RNA sequencing on samples from various stages of MM and characterized the reprogramming of macrophages during disease progression (102). They also emphasized the strong correlation between CD47 and macrophage inhibitory factor (MIF) expression with disease advancement and unfavorable prognosis.…”

“…Li et al. performed single-cell RNA sequencing on samples from various stages of MM and characterized the reprogramming of macrophages during disease progression ( 102 ). They also emphasized the strong correlation between CD47 and macrophage inhibitory factor (MIF) expression with disease advancement and unfavorable prognosis.…”

The tumor immune microenvironment remodeling and response to HER2‐targeted therapy in HER2‐positive advanced gastric cancer

“…40,47 B lymphocytes also interacted with M2 macrophages subsets using CD74-APP/COPA/MIF, which inhibited the M2 macrophages and Tregs from inducing immune resistance. 40,48,49 However, M2 macrophages could interact with B lymphocytes or NK cells through LGASL9-CD44, 40 LTBR-LTB, 50 SIRPA-CD47, 48 SPP1-CD44, 51 and HLE-KLRC1/KLRC2. 52 Tregs employed KLRB1-CLEC2D to interact with B lymphocytes and NK cells, 53 which could also induce immune resistance.…”