RNA-seq analysis between RIS and RIS groups and some subtypes.(A) Venn plot showing differentially expressed genes (DEG) of FS and OS subtype comparison between RIS and SARC groups.(B) Volcano plot showing up-regulated and down-regulated genes in the RIFS group versus the RIOS group.(C) GO pathway enrichment of mRNA-seq between the RIS group and SARC group, and between the RIFS and RIOS subtypes.(D) Relative abundances of activated immune cells and immunosuppression-related cells in subtypes of RIS and primary sarcomas.
Funding
National Key Research and Development Program of China (NKPs)
National Natural Science Foundation of China (NSFC)
ARTICLE ABSTRACT
Radiation-induced sarcomas (RIS) have a poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration.
Here, we performed whole-exome sequencing (WES) and mRNA sequencing (mRNA-seq) on patients with RIS and primary sarcomas (WES samples 46 vs. 48, mRNA-seq samples 16 vs. 8, mainly in head and neck), investigated the antitumor effect of programmed cell death protein 1 (PD-1) blockade in RIS patient-derived xenograft models, and analyzed clinical data of patients with RIS treated with chemotherapy alone or combined with an anti–PD-1 antibody.
Compared with primary sarcomas, RIS manifested different patterns of copy-number variations, a significantly higher number of predicted strong MHC-binding neoantigens, and significantly increased immune cell infiltration. Clinical data showed that the combinatorial use of chemotherapy and PD-1 blockade achieved a higher objective response rate (36.67% vs. 8.00%; P = 0.003), longer overall survival (31.9 months vs. 14.8 months; P = 0.014), and longer progression-free survival (4.7 months vs. 9.5 months; P = 0.032) in patients with RIS compared with single chemotherapy.
Elevated genomic instability and higher immune cell infiltrations were found in RIS than in primary sarcomas. Moreover, higher efficacy of chemotherapy plus PD-1 blockade was observed in animal experiments and clinical practice. This evidence indicated the promising application of immune checkpoint inhibitors in the treatment of RIS.
