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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
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-22 , DOI: 10.1002/advs.202302498 Qiangda Chen 1 , Hanlin Yin 1 , Junyi He 1 , Yuqi Xie 1 , Wenquan Wang 1 , Huaxiang Xu 1 , Lei Zhang 1 , Chenye Shi 1 , Jun Yu 2 , Wenchuan Wu 1 , Liang Liu 1 , Ning Pu 1 , Wenhui Lou 1
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-22 , DOI: 10.1002/advs.202302498 Qiangda Chen 1 , Hanlin Yin 1 , Junyi He 1 , Yuqi Xie 1 , Wenquan Wang 1 , Huaxiang Xu 1 , Lei Zhang 1 , Chenye Shi 1 , Jun Yu 2 , Wenchuan Wu 1 , Liang Liu 1 , Ning Pu 1 , Wenhui Lou 1
Affiliation
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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.
中文翻译：
肿瘤微环境响应性 CD8+ T 细胞和骨髓源性抑制细胞触发基于 CD73 抑制剂 AB680 的胰腺癌协同治疗
CD73 在胰腺导管腺癌 (PDAC) 的发病机制和免疫逃逸中发挥着关键作用。 AB680 是一种极其有效的选择性 CD73 抑制剂，在一项早期临床试验中与吉西他滨和抗 PD-1 疗法联合用于治疗 PDAC。然而，AB680单药治疗PDAC的具体疗效和微环境内的免疫调节尚未完全阐明。在这项研究中，AB680 在增强反应性 CD8 + T 细胞的浸润并延长皮下和原位小鼠 PDAC 模型中的存活方面表现出显着效果。与此同时，它还通过肿瘤源性 CXCL5 以 AMP 依赖性方式促进骨髓源性抑制细胞 (MDSC) 的趋化性，这可能有助于增强免疫抑制。同时施用 AB680 和 PD-1 阻断剂（而不是吉西他滨）可协同抑制肿瘤生长。值得注意的是，吉西他滨削弱了 AB680 的功效，而 AB680 依赖于 CD8 + T 细胞。最后，验证了补充 CXCR2 抑制剂与 AB680 加 PD-1 抑制剂联合使用时可进一步增强治疗效果。这些发现系统地证明了AB680的功效和免疫调节机制，为PDAC提供了一种新颖、高效、有前景的免疫治疗组合策略。
更新日期：2023-10-22
中文翻译：
肿瘤微环境响应性 CD8+ T 细胞和骨髓源性抑制细胞触发基于 CD73 抑制剂 AB680 的胰腺癌协同治疗
CD73 在胰腺导管腺癌 (PDAC) 的发病机制和免疫逃逸中发挥着关键作用。 AB680 是一种极其有效的选择性 CD73 抑制剂，在一项早期临床试验中与吉西他滨和抗 PD-1 疗法联合用于治疗 PDAC。然而，AB680单药治疗PDAC的具体疗效和微环境内的免疫调节尚未完全阐明。在这项研究中，AB680 在增强反应性 CD8 + T 细胞的浸润并延长皮下和原位小鼠 PDAC 模型中的存活方面表现出显着效果。与此同时，它还通过肿瘤源性 CXCL5 以 AMP 依赖性方式促进骨髓源性抑制细胞 (MDSC) 的趋化性，这可能有助于增强免疫抑制。同时施用 AB680 和 PD-1 阻断剂（而不是吉西他滨）可协同抑制肿瘤生长。值得注意的是，吉西他滨削弱了 AB680 的功效，而 AB680 依赖于 CD8 + T 细胞。最后，验证了补充 CXCR2 抑制剂与 AB680 加 PD-1 抑制剂联合使用时可进一步增强治疗效果。这些发现系统地证明了AB680的功效和免疫调节机制，为PDAC提供了一种新颖、高效、有前景的免疫治疗组合策略。
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