Niu Nan, Li Keyu, Wang Junke, Funes Vanessa, Espinoza Birginia, Li Pan, Wang Jianxin, Lyman Melissa, He Mengni, Herbst Brian, Wichroski Michael, Novosiadly Ruslan, Shoucair Sami, Mou Yiping, Zheng Lei
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310003, China.
Biomark Res. 2025 Jan 27;13(1):21. doi: 10.1186/s40364-024-00721-7.
The combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.
We thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.
We found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8 T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86 mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways.
This study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.
传统化疗与免疫检查点抑制剂（ICI）联合治疗胰腺导管腺癌（PDAC）尚未取得成功。给予最大耐受剂量的化疗药物可能具有免疫抑制作用。
因此，我们利用PDAC的临床前模型，包括基因工程小鼠KPC自发性胰腺肿瘤模型和胰腺KPC肿瘤原位植入模型，分别测试了合成的天然免疫激动剂（包括STING和NLRP3激动剂）与ICI联合或不联合化疗的效果。
我们发现天然激动剂可增强化疗在诱导效应T细胞方面的作用，并随后更好地为ICI治疗准备肿瘤微环境（TME）。化疗、天然激动剂和ICI的三联组合在抗肿瘤疗效方面优于单一或双药联合方案。在天然激动剂中加入化疗可增强总体CD8 T细胞和记忆性细胞毒性亚型的浸润。NLRP3激动剂在驱动T细胞耗竭方面的作用小于STING激动剂。在天然激动剂中加入化疗可增强肿瘤中树突状细胞（DC）和肿瘤引流淋巴结中CD86成熟DC的浸润。对胰腺肿瘤的RNA测序分析表明，STING/NLRP3激动剂与化疗联合使用（而非单独使用任何一种治疗方式）在上调T细胞活化信号方面的作用。NLRP3激动剂介导的T细胞活化可能是通过调节氮代谢途径实现的。
本研究支持分别对STING和NLRP3激动剂与化疗联合进行临床试验，以使PDAC患者对ICI治疗敏感。
