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

PURPOSE: Radiation therapy (RT) is a mainstay of cancer care, and accumulating evidence suggests the potential for synergism with components of the immune response. However, few data describe the tumor immune contexture in relation to RT sensitivity. To address this challenge, we used 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. METHODS AND MATERIALS: 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 combined with single sample gene set enrichment analysis. 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 = 2368) 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 nonunimodal distributions (eg, colon, renal, lung, prostate, esophagus, pancreas, and PAM50 breast subtypes; P < .05). Across all tumor types, stratifying RSI at a tumor type-specific median identified 7148 differentially expressed genes, of which 146 were coordinate in direction. Network topology analysis demonstrates RSI measures a coordinated STAT1, IRF1, and CCL4/MIP-1ß transcriptional network. Tumors with an estimated high sensitivity to RT demonstrated distinct enrichment of interferon-associated signaling pathways and immune cell infiltrates (eg, CD8+ T cells, activated natural killer cells, M1-macrophages; q < 0.05), which was in the context of diverse expression patterns of various immunoregulatory molecules. CONCLUSIONS: This analysis describes the immune microenvironments of patient tumors in relation to the RSI gene expression signature.

Tumor-immune ecosystem dynamics define an individual Radiation Immune Score to predict pan-cancer radiocurability.

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy.

Technical Note: A step-by-step guide to Temporally Feathered Radiation Therapy planning for head and neck cancer.

PURPOSE: Prior in silico simulations propose that Temporally Feathered Radiation Therapy (TFRT) may reduce toxicity related to head and neck radiation therapy. In this study we demonstrate a step-by-step guide to TFRT planning with modern treatment planning systems. METHODS: One patient with oropharyngeal cancer planned for definitive radiation therapy using intensity-modulated radiation therapy (IMRT) techniques was replanned using the TFRT technique. Five organs at risk (OAR) were identified to be feathered. A "base plan" was first created based on desired planning target volumes (PTV) coverage, plan conformality, and OAR constraints. The base plan was then re-optimized by modifying planning objectives, to generate five subplans. All beams from each subplan were imported onto one trial to create the composite TFRT plan. The composite TFRT plan was directly compared with the non-TFRT IMRT plan. During plan assessment, the composite TFRT was first evaluated followed by each subplan to meet preset compliance criteria. RESULTS: The following organs were feathered: oral cavity, right submandibular gland, left submandibular gland, supraglottis, and OAR Pharynx. Prescription dose PTV coverage (>95%) was met in each subplan and the composite TFRT plan. Expected small variations in dose were observed among the plans. The percent variation between the high fractional dose and average low fractional dose was 29%, 28%, 24%, 19%, and 10% for the oral cavity, right submandibular, left submandibular, supraglottis, and OAR pharynx nonoverlapping with the PTV. CONCLUSIONS: Temporally Feathered Radiation Therapy planning is possible with modern treatment planning systems. Modest dosimetric changes are observed with TFRT planning compared with non-TFRT IMRT planning. We await the results of the current prospective trial to seeking to demonstrate the feasibility of TFRT in the modern clinical workflow (NCT03768856). Further studies will be required to demonstrate the potential benefit of TFRT over non-TFRT IMRT Planning.