OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Systemic relapse post-radiotherapy and surgery is a primary cause of mortality in sarcoma patients.
• Combining radiotherapy with immunotherapy is a promising strategy to enhance treatment response rates.
• The immune microenvironment of sarcoma remains incompletely understood, hindering targeted immunotherapies.

Purpose of the Study:

• To investigate the tumor immune microenvironment in sarcoma subtypes.
• To identify potential therapeutic targets for immunotherapy by analyzing gene expression and immune cell profiles.
• To explore the role of costimulatory molecules like OX40 and 4-1BB in sarcoma immune responses.

Main Methods:

• Retrospective analysis of sarcoma patients treated with neoadjuvant radiotherapy.
• Utilized The Cancer Genome Atlas (TCGA) data for comprehensive genomic analysis.
• Employed multispectral immunohistochemistry for spatial analysis of tumor immune cells, including T regulatory cells (Tregs).

Main Results:

• Undifferentiated pleomorphic sarcoma (UPS) showed higher expression of immunotherapy targets (CD73, CD39, CD25, 4-1BB) compared to radioresponsive myxoid liposarcoma (MLPS).
• 4-1BB expression correlated with an inflamed and exhausted tumor immune phenotype.
• OX40 and 4-1BB exhibited distinct immune profiles in sarcoma and other cancers, and spatial analysis revealed diverse OX40+ Treg phenotypes.

Conclusions:

• Sarcoma subtypes possess distinct immune characteristics that influence radioresponsiveness.
• Selected sarcoma patients may benefit from immunotherapy, with 4-1BB and OX40 as potential biomarkers.
• Spatial profiling of OX40+ Tregs and tertiary lymphoid structures (TLSs) could enhance patient stratification for immunotherapy.