结缔组织增生
癌症研究
医学
胰腺癌
吉西他滨
癌症
癌相关成纤维细胞
纤维化
肿瘤微环境
内科学
作者
Duk Ki Kim,Juhee Jeong,Dong Sun Lee,Do Young Hyeon,Geon Woo Park,Suwan Jeon,Kyoung Bun Lee,Jin‐Young Jang,Daehee Hwang,Ho Min Kim,Keehoon Jung
标识
DOI:10.1038/s41467-022-33991-6
摘要
Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or immunotherapy modalities. Herein, we reveal that chemotherapy upregulates placental growth factor (PlGF), which directly activates cancer-associated fibroblasts (CAFs) to induce fibrosis-associated collagen deposition in PDAC. Patients with poor prognosis have high PIGF/VEGF expression and an increased number of PIGF/VEGF receptor-expressing CAFs, associated with enhanced collagen deposition. We also develop a multi-paratopic VEGF decoy receptor (Ate-Grab) by fusing the single-chain Fv of atezolizumab (anti-PD-L1) to VEGF-Grab to target PD-L1-expressing CAFs. Ate-Grab exerts anti-tumor and anti-fibrotic effects in PDAC models via the PD-L1-directed PlGF/VEGF blockade. Furthermore, Ate-Grab synergizes with gemcitabine by relieving desmoplasia. Single-cell RNA sequencing identifies that a CD141+ CAF population is reduced upon Ate-Grab and gemcitabine combination treatment. Overall, our results elucidate the mechanism underlying chemotherapy-induced fibrosis in PDAC and highlight a combinatorial therapeutic strategy for desmoplastic cancers.
科研通智能强力驱动
Strongly Powered by AbleSci AI