通过全身给药克服胰腺癌瘤内注射 STING 激动剂的挑战

IF 29.5 1区 医学 Q1 HEMATOLOGY
Keyu Li, Junke Wang, Rui Zhang, Jiawei Zhou, Birginia Espinoza, Nan Niu, Jianxin Wang, Noelle Jurcak, Noah Rozich, Arsen Osipov, MacKenzie Henderson, Vanessa Funes, Melissa Lyman, Alex B. Blair, Brian Herbst, Mengni He, Jialong Yuan, Diego Trafton, Chunhui Yuan, Michael Wichroski, Xubao Liu, Juan Fu, Lei Zheng
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引用次数: 0

摘要

由于瘤内给药面临挑战,先天性激动剂在大多数肿瘤类型中的疗效测试尚未超越临床前研究。胰腺导管腺癌(PDAC)的肿瘤微环境恶劣,导致 T 细胞功能失调。先天性激动剂治疗可作为一种 T 细胞启动机制,使 PDAC 对抗 PD-1 抗体(a-PD-1)治疗敏感。我们利用一种自发形成肝转移的移植小鼠模型、一种自发发生 PDAC 的基因工程 KPC 小鼠模型和一种源自人类患者的异种移植模型,比较了新一代 STING 激动剂 BMS-986301 在肝内/瘤内给药和肌肉注射全身给药之间的抗肿瘤疗效。流式细胞术、Nanostring 和细胞因子检测被用来评估局部和全身免疫反应。这项研究表明,通过肌肉注射全身给药 STING 激动剂与其瘤内注射在诱导效应 T 细胞反应和抗肿瘤疗效方面效果相当。与瘤内给药相比,全身给药诱导的 T 细胞衰竭和免疫抑制信号均有所减弱。尽管如此,无论是瘤内给药还是全身给药 STING 激动剂,都会增加肿瘤浸润 T 细胞 CTLA-4 的表达。然而,在KPC小鼠自发性PDAC模型中,a-PD-1和抗CTLA-4抗体与全身性STING激动剂的结合显示了抗肿瘤疗效。用 PBMC 重组人源异种移植物的小鼠胰腺和肝脏正位模型也显示,瘤内和肌内 STING 激动剂的抗肿瘤和脱落效应相当。综上所述,本研究支持通过全身给药治疗 PDAC 的先天性激动剂的临床开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration
Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC.
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来源期刊
CiteScore
48.10
自引率
2.10%
发文量
169
审稿时长
6-12 weeks
期刊介绍: The Journal of Hematology & Oncology, an open-access journal, publishes high-quality research covering all aspects of hematology and oncology, including reviews and research highlights on "hot topics" by leading experts. Given the close relationship and rapid evolution of hematology and oncology, the journal aims to meet the demand for a dedicated platform for publishing discoveries from both fields. It serves as an international platform for sharing laboratory and clinical findings among laboratory scientists, physician scientists, hematologists, and oncologists in an open-access format. With a rapid turnaround time from submission to publication, the journal facilitates real-time sharing of knowledge and new successes.
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