Li Keyu, Wang Junke, Zhang Rui, Zhou Jiawei, Espinoza Birginia, Niu Nan, Wang Jianxin, Jurcak Noelle, Rozich Noah, Osipov Arsen, Henderson MacKenzie, Funes Vanessa, Lyman Melissa, Blair Alex B, Herbst Brian, He Mengni, Yuan Jialong, Trafton Diego, Yuan Chunhui, Wichroski Michael, Liu Xubao, Fu Juan, Zheng Lei
Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
J Hematol Oncol. 2024 Aug 7;17(1):62. doi: 10.1186/s13045-024-01576-z.
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.
由于瘤内给药面临挑战，在大多数肿瘤类型中，天然激动剂尚未超越临床前研究阶段进行疗效测试。胰腺导管腺癌（PDAC）具有恶劣的肿瘤微环境，可导致T细胞功能失调。天然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。我们使用具有自发形成肝转移的移植小鼠模型、自发发展为PDAC的基因工程KPC小鼠模型以及人源肿瘤异种移植模型，比较了下一代STING激动剂BMS-986301肝内/瘤内给药与肌肉内全身给药的抗肿瘤疗效。采用流式细胞术、Nanostring技术和细胞因子检测来评估局部和全身免疫反应。本研究表明，通过肌肉内注射全身给药STING激动剂在诱导效应T细胞反应和抗肿瘤疗效方面等同于瘤内注射。与瘤内给药相比，全身给药诱导的T细胞耗竭和免疫抑制信号有所减弱。尽管如此，STING激动剂的瘤内或全身治疗均与肿瘤浸润T细胞上CTLA-4表达增加有关。然而，a-PD-1和抗CTLA-4抗体与全身STING激动剂联合使用在KPC小鼠自发PDAC模型中显示出抗肿瘤疗效。用人外周血单核细胞重建的人源肿瘤异种移植小鼠胰腺和肝脏原位模型也表明，瘤内和肌肉内STING激动剂的抗肿瘤和远隔效应是等效的。综上所述，本研究支持通过全身给药进行天然激动剂治疗PDAC的临床开发。
