Oncolytic reovirus enhances the effect of CEA immunotherapy when combined with PD1-PDL1 inhibitor by reducing the immunosuppressive tumor microenvironment in a colorectal cancer model

Abstract

Abstract Immunotherapy is a type of tumor treatment that increases anti-tumor immunity to inhibit tumor growth. By enhancing the immune response through the lysis of tumor cells with an oncolytic virus and inhibiting the immune system's inhibitory reactions, the effectiveness of immunotherapy can be improved. In this study on a mouse model of colorectal cancer, the efficacy of oncolytic reovirus in a combined treatment with an adenovector expressing carcinoembryonic antigen (CEA) and PD-1/PD-L1 inhibitor was evaluated. The tumorized mice with CEA-expressing CT26 cells were immunized with a constructed adenovector expressing CEA along with PD-1/PD-L1 inhibitor. Then three doses of reovirus were injected into the tumor. On day of 26th, all mice were sacrificed, and tumor size, histopathological findings, and immune response to tumor antigens were compared among treatment groups. The results showed that immunization with CEA, combined with treatment with reovirus and PD-1/PD-L1 inhibitor, resulted in the lowest tumor growth among the treated groups. Additionally, the combined treatment group exhibited the highest level of cytotoxic immunity. This treatment also led to a decrease in Foxp3 in the tumor microenvironment and TNF-α secretion compared to other groups. Furthermore, through the production of IFN-γ and increased cytotoxic effect, it was demonstrated that the cellular immune system works more efficiently. Histopathological evaluations revealed the lowest number of mitosis and the highest amount of tumor-infiltrating lymphocytes (TILs) in this group. In conclusion, although the combination of tumor vaccines with oncolytic viruses improves treatment efficacy, inhibiting the PD-1/PD-L1 interaction can further enhance immunovirotherapy efficacy by reducing immunosuppressive effects boosted by the virus activity, and stimulating the immune system. This approach, in combination with other treatment methods, shows promise in controlling tumor growth.