The Radiosensitivity Index Gene Signature Identifies Distinct Tumor Immune Microenvironment Characteristics Associated With Susceptibility to Radiation Therapy

PURPOSE: Radiotherapy (RT) is a mainstay of cancer care and accumulating evidence suggests the potential for synergism with components of the immune response. However, little data describes the tumor immune contexture in relation to RT-sensitivity. To address this challenge, we employed the radiation sensitivity index (RSI) gene signature to estimate the RT-sensitivity of >10,000 primary tumors and characterized their immune microenvironments in relation to the RSI. MATERIAL AND METHODS: We analyzed gene expression profiles of 10,469 primary tumors (31 types) within a prospective tissue collection protocol. The RT-sensitivity of each tumor was estimated by the RSI and respective distributions were characterized. The tumor biology measured by the RSI was evaluated by differentially expressed genes (DEGs) combined with single sample gene set enrichment analysis (ssGSEA). Differences in the expression of immune regulatory molecules were assessed and deconvolution algorithms were used to estimate immune cell infiltrates in relation to the RSI. A subset (n=2,368) of tumors underwent DNA sequencing for mutational frequency characterization. RESULTS: We identified a wide range of RSI values within and across various tumor types, with several demonstrating non-unimodal distributions (e.g. colon, renal, lung, prostate, esophagus, pancreas and PAM50 breast subtypes; p