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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.

Authors :
Chen, Qiangda
Yin, Hanlin
He, Junyi
Xie, Yuqi
Wang, Wenquan
Xu, Huaxiang
Zhang, Lei
Shi, Chenye
Yu, Jun
Wu, Wenchuan
Liu, Liang
Pu, Ning
Lou, Wenhui
Source :
Advanced Science; 11/24/2023, Vol. 10 Issue 33, p1-16, 16p
Publication Year :
2023

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
21983844
Volume :
10
Issue :
33
Database :
Complementary Index
Journal :
Advanced Science
Publication Type :
Academic Journal
Accession number :
173824418
Full Text :
https://doi.org/10.1002/advs.202302498