Distinct Sarcoma Microenvironments Predict Benefit from Addition of Pembrolizumab to Preoperative Radiotherapy and...

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Stage III undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS) have poor prognoses.
• Preoperative radiotherapy (RT) combined with pembrolizumab showed improved disease-free survival (DFS) in the SU2C-SARC032 trial.

Purpose of the Study:

• To identify predictive biomarkers for pembrolizumab plus RT response in UPS and LPS.
• To elucidate the mechanisms of response and resistance to this combination therapy.

Main Methods:

• Comprehensive multi-omics profiling (bulk RNA-seq, flow cytometry, CyTOF) of pre- and post-treatment tumor and blood samples.
• Single-cell RNA-seq atlas construction (65,786 cells) to define sarcoma subtypes.
• Digital cytometry to deconvolute single-cell states from bulk data.

Main Results:

• Two distinct tumor microenvironments (TMEs) – immune-cold SE1 and immune-hot SIC E – responded differently to pembrolizumab.
• Pembrolizumab plus RT modulated T cell populations, depleting exhausted T cells in SIC E and increasing effector T cells in SE1.
• Matrix-remodeling and epithelial-like sarcoma cell programs correlated with worse outcomes and were reduced by treatment.

Conclusions:

• Sarcoma TME signatures can predict response to pembrolizumab combined with preoperative RT.
• Different immune mechanisms underlie response in distinct TME subtypes.
• This study provides insights into personalized immunotherapy strategies for high-risk sarcomas.