Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune...

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Radiation-induced sarcomas (RIS) present a significant clinical challenge with limited effective treatment options.
• The genomic landscape and tumor microenvironment of RIS remain underexplored, hindering therapeutic development.

Purpose of the Study:

• To characterize the genomic and immune profiles of RIS.
• To evaluate the efficacy of programmed cell death protein 1 (PD-1) blockade in treating RIS.

Main Methods:

• Whole-exome sequencing (WES) and mRNA sequencing (mRNA-seq) were performed on RIS and primary sarcoma samples.
• Patient-derived xenograft models were used to assess the antitumor effects of PD-1 blockade.
• Clinical data from RIS patients treated with chemotherapy alone or in combination with anti-PD-1 therapy were analyzed.

Main Results:

• RIS exhibited distinct copy-number variation patterns, a higher number of predicted neoantigens, and increased immune cell infiltration compared to primary sarcomas.
• Combination therapy (chemotherapy + PD-1 blockade) resulted in a higher objective response rate (36.67% vs. 8.00%), longer overall survival (31.9 vs. 14.8 months), and longer progression-free survival (9.5 vs. 4.7 months) compared to chemotherapy alone.
• P-values: P = 0.003 for ORR, P = 0.014 for OS, P = 0.032 for PFS.

Conclusions:

• RIS is characterized by elevated genomic instability and heightened immune cell infiltration.
• Chemotherapy combined with PD-1 blockade demonstrates superior efficacy in both preclinical models and clinical practice for RIS treatment.
• Immune checkpoint inhibitors show promising therapeutic potential for radiation-induced sarcomas.