Abstract
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, CD3+T, CD4+T, and CD8+T cells increased. Compared to VV-ΔTK treatment, VV-ΔTK-4L further increases the number of CD8+T cells with effector phenotypes, and downregulates exhaustion-related molecules on CD8+T cells, and does not increase the proportion of Foxp3+T 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.