Interferon signaling underlies radiotherapy responses in malignant peripheral nerve sheath tumors (MPNSTs)

Malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. Here, we combine bulk and single cell transcriptomics, genome wide CRISPRi screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and human patient samples to understand the mediators of radiation response. Our data reveal MPNSTs induce a type I interferon signature that functionally underlies radiation response. Moreover, irradiation of immunocompetent mouse MPNST allografts leads to interferon mediated T-cell recruitment and activation. Analysis of human MPNST resection specimens demonstrates increased microenvironmental and CD8+ T-cell infiltration are associated with improved local control following radiotherapy while chromosome 9p loss, which harbors an interferon gene cluster, is associated with poor radiotherapy response and decreased CD8+ T-cell infiltration. Taken together, these results provide preclinical rationale for combining immunomodulatory agents targeting interferon signaling to improve radiation responses in MPNSTs, which may be broadly applicable to other soft tissue sarcomas.