Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer [II]. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer [II]

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: A total of 20 samples, with 4 replicates in 5 groups

标准癌症治疗仅靶向肿瘤细胞，却未考量其可能对肿瘤微环境造成的附带损伤，而此类损伤可能削弱治疗应答效果。本研究借助患者来源肿瘤类器官（patient-derived tumor organoids）、原代基质细胞，或新型小鼠直肠癌模型，证实肿瘤细胞分泌的IL-1α可将癌相关成纤维细胞（cancer-associated fibroblasts, CAFs）极化为促炎表型，经由活性氮族（reactive nitrogen species, NOS）介导引发氧化DNA损伤加剧，进而使炎性CAFs（inflammatory CAFs, iCAFs）对p53介导的治疗诱导性衰老更为敏感；该过程会触发细胞外基质蛋白组（matrisome）组成改变，最终导致放化疗耐药与疾病进展。因此，抑制IL-1信号通路、阻断iCAFs衰老或采用衰老细胞清除疗法，可使小鼠对放射治疗更为敏感。值得注意的是，对放射治疗应答不佳的直肠癌患者，其体内CAFs数量增多、炎性CAFs基因特征谱占主导，且血清白细胞介素1受体拮抗剂（IL-1RA）水平更低。基线IL1RA基因低表达可预示不良预后，而血清IL-1RA水平与IL1RA基因位点的单核苷酸多态性（single nucleotide polymorphism, SNP）rs4251961 T/C相关。此外，患者肿瘤类器官的条件培养基可使成纤维细胞以IL-1依赖的方式，对辐射诱导的衰老更为敏感。综上，本研究阐明了炎性CAFs在癌症治疗中的关键作用，并确定IL-1信号通路可作为基质细胞复极化与阻断CAFs衰老的潜在治疗靶点。整体实验设计：共计20份样本，分为5组，每组设置4个生物学重复。