中性粒细胞胞外陷阱
癌症研究
胰腺癌
白细胞介素17
免疫检查点
封锁
肿瘤微环境
癌症
免疫学
生物
免疫疗法
免疫系统
炎症
受体
遗传学
生物化学
作者
Yu Zhang,Vidhi Chandra,Erick Riquelme,Prasanta Dutta,P Quesada,Amanda Rakoski,Michelle Zoltan,Nivedita Arora,Seyda Baydogan,William Horne,Jared K. Burks,Hanwen Xu,S. Perwez Hussain,Huamin Wang,Sonal Gupta,Anirban Maitra,Jennifer M. Bailey,Seyed Javad Moghaddam,Sulagna Banerjee,İsmet Şahin,Pratip K. Bhattacharya,Florencia McAllister
摘要
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
科研通智能强力驱动
Strongly Powered by AbleSci AI