Type I Interferons: Unraveling their Role in the Response to Short Course Radiotherapy in Rectal Cancer 3621

Abstract Description Colorectal Cancer (CRC) is a devastating malignancy that ranks as the second leading cause of cancer-related deaths. Rectal cancer (RC) comprises one-third of CRC cases, with over 50,000 people in the US diagnosed each year. Short course radiotherapy (SCRT) is being investigated as a curative treatment option for RC, with the aim to preserve organ function and avoid excision surgery. SCRT can significantly reduce tumor burden in a subset of patients, however most patients’ tumors do not respond. What dictates this divide is poorly understood. We developed an orthotopic murine model of RC that recapitulates human tumors. In this model, administration of SCRT results in some mice that exhibit a reduction of tumor burden (responders), and a group of mice whose tumor respond poorly (nonresponders). RNA-sequencing of intratumoral cell populations revealed upregulation of the Type I Interferon (IFN) signaling pathway in responder tumors compared to nonresponders. Preliminary data confirmed that responder tumors had higher concentrations of intratumoral Type I IFN protein. Blockade of Type I IFN receptors completely abrogated the responder phenotype, emphasizing the importance of these factors in dictating the responder/nonresponder divide. We translated these findings to a therapeutic intervention where tumors were treated concurrently with SCRT and a Type I IFN agonist. Combination treatment resulted in a higher percentage of responder tumors and improved treatment efficacy. Funding Sources T32AI007285 Wilmot Predoctoral Fellowship Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)