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Tumor Microenvironment Responsive CD8+ T Cells and Myeloid‐Derived Suppressor Cells to Trigger CD73 Inhibitor AB680‐Based Synergistic Therapy for Pancreatic Cancer

癌症研究 吉西他滨 肿瘤微环境 胰腺癌 CD8型 免疫抑制 髓源性抑制细胞 免疫系统 医学 髓系白血病 细胞毒性T细胞 癌症 免疫学 药理学 化学 抑制器 内科学 体外 生物化学
作者
Qiangda Chen,Hanlin Yin,Junyi He,Yu Xie,Wenquan Wang,Huaxiang Xu,Lei Zhang,Chenye Shi,Jun Yu,Wen-Chuan Wu,Liang Liu,Ning Pu,Wenhui Lou
出处
期刊:Advanced Science [Wiley]
标识
DOI:10.1002/advs.202302498
摘要

Abstract CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti‐PD‐1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8 + T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid‐derived suppressor cells (MDSCs) by tumor‐derived CXCL5 in an AMP‐dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD‐1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8 + T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD‐1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.
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