Ju Yushi, Dai Feiyu, Wang Yirong, Ye Zhenyu, Li Yang, Ju Songguang, Ge Yan, Chen Wei
Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China.
Department of Immunology, Basic Medical College, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Medical Biotechnology Institute, Soochow University, Suzhou, Jiangsu 215123, China; Collaborative Innovation Center of Bone and Immunology between Sihong Hospital and Soochow University, Suzhou 215123, China.
Transl Oncol. 2024 Dec;50:102151. doi: 10.1016/j.tranon.2024.102151. Epub 2024 Oct 9.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a poor prognosis. Mono-immunotherapy, such as blockade of the PD-1/PD-L1 pathway, for PDAC has proven to be less effective. The systemic exertion of 4-1BB signaling enhanced antitumor immunity accompanied by hepatotoxicity, which is an obstacle for its clinical application. Our study exploits an oncolytic virus armed with 4-1BBL (VV-ΔTK-4L) to locally express 4-1BBL in the tumor microenvironment (TME), thus avoiding hepatotoxicity. VV-ΔTK-4L prolonged the survival time of a pancreatic tumor mouse model and modified the immune status of the TME and spleen. In the TME, the quantities of CD45 cells, NK1.1 cells, CD11c DCs, CD3T, CD4T, and CD8T cells increased. Compared to VV-ΔTK treatment, VV-ΔTK-4L further increases the number of CD8T cells with effector phenotypes, and downregulates exhaustion-related molecules on CD8T cells, and does not increase the proportion of Foxp3T cells. Thus, the TME of pancreatic cancer was converted from "cold" to "hot" by VV-ΔTK-4L. Blockade of the PD-1/PD-L1 pathway combined with VV-ΔTK-4L further significantly improves the survival ratio of a tumor-bearing mouse model. This study provides a systemic therapeutic strategy and approach for PDAC immunotherapy.
胰腺导管腺癌（PDAC）是一种预后很差的高致死性疾病。事实证明，针对PDAC的单免疫疗法，如阻断PD-1/PD-L1通路，效果较差。4-1BB信号的全身应用增强了抗肿瘤免疫力，但伴有肝毒性，这是其临床应用的一个障碍。我们的研究利用一种携带4-1BBL的溶瘤病毒（VV-ΔTK-4L）在肿瘤微环境（TME）中局部表达4-1BBL，从而避免肝毒性。VV-ΔTK-4L延长了胰腺肿瘤小鼠模型的存活时间，并改变了TME和脾脏的免疫状态。在TME中，CD45细胞、NK1.1细胞、CD11c DCs、CD3T、CD4T和CD8T细胞的数量增加。与VV-ΔTK治疗相比，VV-ΔTK-4L进一步增加了具有效应表型的CD8T细胞数量，下调了CD8T细胞上与耗竭相关的分子，并且没有增加Foxp3T细胞的比例。因此，VV-ΔTK-4L将胰腺癌的TME从“冷”转化为“热”。阻断PD-1/PD-L1通路与VV-ΔTK-4L联合使用进一步显著提高了荷瘤小鼠模型的存活率。本研究为PDAC免疫治疗提供了一种系统性的治疗策略和方法。
