Senescence-induced vascular remodeling creates new therapeutic vulnerabilities in pancreas cancer

KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB)-mediated senescence, a tumor suppressive process accompanied by a non-cell autonomous program defined as the senescence-associated secretory phenotype (SASP). In genetically and histopathologically accurate mouse models of PDAC, this senescence-inducing therapy produces a SASP that includes pro-angiogenic factors that promote tumor vascularization, culminating in enhanced drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8 + T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC, therapy- induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.

KRAS突变型胰腺导管腺癌（KRAS mutant pancreatic ductal adenocarcinoma, PDAC）以促结缔组织增生反应为特征，该反应可诱导血管生成低下、免疫抑制，并导致化疗与免疫治疗耐药。本研究证实，靶向KRAS致癌信号通路的MEK及CDK4/6抑制剂联合方案，可通过诱导视网膜母细胞瘤（retinoblastoma, RB）介导的细胞衰老抑制PDAC增殖；细胞衰老是一种肿瘤抑制过程，伴随被称为衰老相关分泌表型（senescence-associated secretory phenotype, SASP）的非细胞自主程序。在基因与组织病理学层面精准匹配的PDAC小鼠模型中，该促衰老治疗可诱导产生包含促血管生成因子的SASP，后者可促进肿瘤血管生成，最终增强药物递送效率并提升细胞毒性吉西他滨化疗的疗效。此外，SASP介导的内皮细胞活化可促使CD8阳性T细胞浸润原本免疫“冷”的肿瘤组织，使肿瘤对PD-1检查点阻断疗法敏感。综上，在PDAC中，治疗诱导的细胞衰老可通过SASP依赖的方式作用于肿瘤血管系统与免疫系统，从而赋予原本无效的化疗与免疫治疗新的敏感性。