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posted on 2023-10-24, 14:20 authored by Lindy L. Visser, Margit Bleijs, Thanasis Margaritis, Marc van de Wetering, Frank C. P. Holstege, Hans Clevers Schematic overview mechanism of Ewing sarcoma cells shaping the immune microenvironment into an immunosuppressive niche. (1) Immunomodulatory interactions between Ewing sarcoma cells and myeloid cells induce polarization of macrophages to an immunosuppressive, M2-like, phenotype and induce tolerogenic DCs. (2) Immunosuppressive macrophage interacts with T cell, where, for example, TIGIT–NECTIN2 interactions leads to the inhibition of T-cell activation resulting in a suppressed/dysfunctional T cell. (3) Tolerogenic DC interacts with naïve T cells but is lacking expression of costimulatory molecules, important for T-cell priming, resulting in a tolerogenic T cell. (4) T cell interacts with Ewing sarcoma cell, but because of it tolerogenic state the T cell is unable to activate, produce cytokines, and proliferate which are essential for cancer cell killing. Image created using BioRender.
Funding
Stichting Kinderen Kankervrij (KiKa)
Oncode Institute
History
ARTICLE ABSTRACT
Novel therapeutic strategies are urgently needed for patients with high-risk Ewing sarcoma and for the reduction of severe side effects for all patients. Immunotherapy may fill this need, but its successful application has been hampered by a lack of knowledge on the composition and function of the Ewing sarcoma immune microenvironment. Here, we explore the immune microenvironment of Ewing sarcoma, by single-cell RNA sequencing of 18 Ewing sarcoma primary tissue samples. Ewing sarcoma is infiltrated by natural killer, T, and B cells, dendritic cells, and immunosuppressive macrophages. Ewing sarcoma–associated T cells show various degrees of dysfunction. The antigen-presenting cells found in Ewing sarcoma lack costimulatory gene expression, implying functional impairment. Interaction analysis reveals a clear role for Ewing sarcoma tumor cells in turning the Ewing sarcoma immune microenvironment into an immunosuppressive niche. These results provide novel insights into the functional state of immune cells in the Ewing sarcoma tumor microenvironment and suggest mechanisms by which Ewing sarcoma tumor cells interact with, and shape, the immune microenvironment.
This study is the first presenting a detailed analysis of the Ewing sarcoma microenvironment using single-cell RNA sequencing. We provide novel insight into the functional state of immune cells and suggests mechanisms by which Ewing tumor cells interact with, and shape, their immune microenvironment. These insights provide help in understanding the failures and successes of immunotherapy in Ewing sarcoma and may guide novel targeted (immuno) therapeutic approaches.
