EWS-FLI1 low Ewing sarcoma cells demonstrate decreased susceptibility to T-cell-mediated tumor cell apoptosis
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Kelly M. Bailey1, Claire M. Julian1, Ariel N. Klinghoffer1, Heather Bernard1, Peter C. Lucas2 and Linda M. McAllister-Lucas1
1 Department of Pediatrics, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
2 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
|Kelly M. Bailey,||email:||Kelly.Bailey@chp.edu|
|Linda M. McAllister-Lucas,||email:||Linda.McAllister@chp.edu|
Keywords: EWS-FLI1; Ewing sarcoma; T-cell; interferon; apoptosis
Abbreviations: CTC: circulating tumor cell; IFN-γ: interferon-gamma; MFI: median fluorescence intensity
Received: January 30, 2019 Accepted: May 02, 2019 Published: May 21, 2019
Metastatic and relapsed Ewing sarcoma typically afflicts the adolescent population and is largely fatal. These bone tumors are most commonly driven by the fusion oncoprotein EWS-FLI1. Ewing tumors demonstrate significant intra-tumoral heterogeneity, and individual tumor cells can express highly variable and dynamic levels of EWS-FLI1. Recent studies revealed that the EWS-FLI1 oncoprotein level (high versus low expression) greatly influences the behavior of Ewing tumor cells. As compared to cells with high EWS-FLI1, Ewing cells in the EWS-FLI1 low state demonstrate an increased propensity for metastasis. In light of these observations, we sought to determine how tumor cell EWS-FLI1 level influences the anti-tumor cell immune response. Since ICAM-1, which can promote tumor cell/T-cell interaction and T-cell activation, is highly expressed on EWS-FLI1 low cells, we hypothesized that EWS-FLI1 low cells would be more susceptible to T-cell mediated tumor cell apoptosis as compared to cells with high EWS-FLI1. Unexpectedly, we found that EWS-FLI1 low cells are more resistant to T-cell mediated apoptosis than EWS-FLI1 high cells. We investigated the potential mechanisms by which EWS-FLI1 level might influence the T-cell anti-tumor response, and discovered that low EWS-FLI1 expression results in upregulation of PD-L1 and PD-L2, both important ligands for the PD-1 immune checkpoint receptor on T-cells. We demonstrated that blocking PD-1 results in a greater increase of T-cell mediated killing of EWS-FLI1 low tumor cells as compared to cells with higher EWS-FLI1 expression. Our studies suggest that Ewing cells in the EWS-FLI1 low expression state may serve as a niche of tumor immune-evasion.
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