Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Cancer Cell. 2022 Feb 14;40(2):168-184.e13. doi: 10.1016/j.ccell.2022.01.004. Epub 2022 Feb 3.

Abstract

Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.

Keywords: IL-1 signalling; IL1RN SNP; cancer-associated fibroblasts; neoadjuvant therapy; rectal cancer; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Cell Line, Tumor
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA Damage
  • Disease Models, Animal
  • Disease Susceptibility
  • Drug Resistance, Neoplasm*
  • Gene Expression Profiling
  • Heterografts
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Mice
  • Neoadjuvant Therapy
  • Prognosis
  • Rectal Neoplasms / drug therapy
  • Rectal Neoplasms / etiology
  • Rectal Neoplasms / metabolism*
  • Rectal Neoplasms / pathology
  • Signal Transduction
  • Tumor Microenvironment* / genetics

Substances

  • Biomarkers
  • Cytokines