Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Standard cancer therapy targets tumor cells while not considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that tumor cell-derived IL-1a polarizes cancer-associated fibroblasts (CAFs) towards a pro-inflammatory phenotype causing an elevated oxidative DNA damage mediated by reactive nitrogen species (NOS) and subsequently sensitizing iCAFs to a p53-mediated therapy-induced senescence, which triggers changes in matrisome composition culminating in chemoradiotherapy resistance and disease progression. Consequently, IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. Importantly, rectal cancer patients with poor response to radiotherapy are characterized by an increased number of CAFs, a dominant inflammatory CAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels. Low baseline IL1RA gene expression predicts poor outcome while IL-1RA serum levels are associated with a single nucleotide polymorphism (SNP) in IL1RA (rs4251961 T/C). Moreover, conditioned supernatant from patient tumor organoids sensitizes fibroblasts to undergo radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for inflammatory CAFs in cancer therapy and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence. Overall design: single-cell RNA-seq of CAFs