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Published on: March 7, 2025
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SARC028 Samples Reveal an Interplay between TGF-β, IFN Signaling, and Low HLA Class I Expression as Contributors to
Jessica D Daley1, Elina Mukherjee2, David Ferraro2
1University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Summary
Ewing sarcoma resists PD1 immunotherapy due to an immunosuppressive tumor microenvironment. This study identified a specific cellular neighborhood associated with poor response, offering targets for improved Ewing sarcoma treatments.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Ewing sarcoma exhibits limited response to PD1-targeted immunotherapy, unlike some adult sarcomas.
- The underlying mechanisms of immunotherapy resistance in Ewing sarcoma are not well understood.
Purpose of the Study:
- To investigate the Ewing sarcoma tumor microenvironment and identify features associated with resistance to PD1 checkpoint inhibition.
- To analyze changes in tumor biopsies before and after pembrolizumab therapy in a phase II clinical trial.
Main Methods:
- Utilized multiplexed immunofluorescence, spatial proteomics, and spatial transcriptomics.
- Analyzed paired pretreatment and posttreatment biopsy specimens from Ewing sarcoma patients in the SARC028 trial.
Main Results:
- Pembrolizumab therapy did not change immune cell infiltration levels but increased immunoregulatory markers.
- Spatial transcriptomics revealed a distinct cellular neighborhood (CN10) linked to poor treatment response.
- CN10 featured tumor cells with high TGF-β response, low IFN response, and low HLA class I expression, correlating with immune infiltration.
Conclusions:
- Identified an immunosuppressive triad in Ewing sarcoma that hinders antitumor immunity.
- Disrupting this triad is a potential strategy to enhance immunotherapy effectiveness in Ewing sarcoma.
- Analysis of paired tumor biopsies from clinical trials provides valuable insights into treatment resistance.
