VISTA drives macrophages towards a pro-tumoral phenotype that promotes cancer cell phagocytosis yet down-regulates T cell responses.

Autor: Lin Y; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Choukrani G; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Dubbel L; Faculty VI, School of Medicine and Health Sciences, Department for human Medicine, Carl von Ossietzky Universität Oldenburg, University Clinic for Gynecology, Oldenburg, Germany., Rockstein L; Faculty VI, School of Medicine and Health Sciences, Department for human Medicine, Carl von Ossietzky Universität Oldenburg, University Clinic for Gynecology, Oldenburg, Germany., Freile JA; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Qi Y; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Wiersma V; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Zhang H; Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, China., Koch KW; Faculty VI, School of Medicine and Health Sciences, Dept. of Neuroscience, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany., Ammatuna E; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Schuringa JJ; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., van Meerten T; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Huls G; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands., Bremer E; Department of Hematology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, 9713 EZ, The Netherlands. e.bremer@umcg.nl.
Jazyk: angličtina
Zdroj: Experimental hematology & oncology [Exp Hematol Oncol] 2024 Mar 29; Vol. 13 (1), pp. 35. Date of Electronic Publication: 2024 Mar 29.
DOI: 10.1186/s40164-024-00501-x
Abstrakt: Background: VISTA is a well-known immune checkpoint in T cell biology, but its role in innate immunity is less established. Here, we investigated the role of VISTA on anticancer macrophage immunity, with a focus on phagocytosis, macrophage polarization and concomitant T cell activation.
Methods: Macrophages, differentiated from VISTA overexpressed THP-1 cells and cord blood CD34 + cell-derived monocytes, were used in phagocytosis assay using B lymphoma target cells opsonized with Rituximab. PBMC-derived macrophages were used to assess the correlation between phagocytosis and VISTA expression. qRT-PCR, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyze the impact of VISTA on other checkpoints and M1/M2-like macrophage biology. Additionally, flow cytometry was used to assess the frequency of CD14 + monocytes expressing VISTA in PBMCs from 65 lymphoma patients and 37 healthy donors.
Results: Ectopic expression of VISTA in the monocytic model cell line THP-1 or in primary monocytes triggered differentiation towards the macrophage lineage, with a marked increase in M2-like macrophage-related gene expression and decrease in M1-like macrophage-related gene expression. VISTA expression in THP-1 and monocyte-derived macrophages strongly downregulated expression of SIRPα, a prominent 'don't eat me' signal, and augmented phagocytic activity of macrophages against cancer cells. Intriguingly, expression of VISTA's extracellular domain alone sufficed to trigger phagocytosis in ∼ 50% of cell lines, with those cell lines also directly binding to recombinant human VISTA, indicating ligand-dependent and -independent mechanisms. Endogenous VISTA expression was predominantly higher in M2-like macrophages compared to M0- or M1-like macrophages, with a positive correlation observed between VISTA expression in M2c macrophages and their phagocytic activity. VISTA-expressing macrophages demonstrated a unique cytokine profile, characterized by reduced IL-1β and elevated IL-10 secretion. Furthermore, VISTA interacted with MHC-I and downregulated its surface expression, leading to diminished T cell activation. Notably, VISTA surface expression was identified in monocytes from all lymphoma patients but was less prevalent in healthy donors.
Conclusions: Collectively, VISTA expression associates with and drives M2-like activation of macrophages with a high phagocytic capacity yet a decrease in antigen presentation capability to T cells. Therefore, VISTA is a negative immune checkpoint regulator in macrophage-mediated immune suppression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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