Olivia Kaneko

Abstract

Cancer remains one of the biggest threats to worldwide human health, even as recent advances in oncology have driven the development of new and combinatorial immunotherapies. Abscopal effects and restored responses to immune checkpoint blockade (ICB) therapies have been observed in a number of cases where radiation therapy (RT) was concurrently given. Recent evidence suggests that interferon-stimulated pathways, capable of releasing cytokines and influencing CD8+ T cells and dendritic cells, could modulate radiation-induced immunity. Individual studies have demonstrated cancer type-specific effects but have not captured expression in a large-scale representative pool of human cancers. To investigate cancer features that predict radiation-induced immune activation, we measured single cell RNA expression in 100 cancer cell lines. Pooled samples were treated with RT or STING (stimulator of interferon genes) agonist DiABZI, and four cell lines were identified to show considerable radiation-induced STING pathway activation: two derived from exocrine ductal adenocarcinoma and two derived from breast carcinoma. Expression of STING pathway downstream proteins MHC-I, PDL-1, and MX1 demonstrated radiation-induced STING activation in three of these cell lines. Time series investigations also unveiled distinct differences in activation curves between radiation and DiABZI treatments. Data from The Cancer Gene Atlas (TCGA) was integrated into our findings to inform cancer traits such as chromosomal instability that may correlate with immune activation. This multi-cancer examination of immune activation via the STING pathway highlights chromosomal and structural aspects of two carcinomas which could modulate the radiation-induced restoration of immune responses.