Recently, a research paper titled “Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine” was published in Cell Reports Medicine, a sub-journal of Cell.
The study demonstrates that a novel oncolytic virus, M1 oncolytic vesicular stomatitis virus (OVM), can enhance the antitumor effect of DC vaccines by increasing the infiltration of CD8+ effector T cells in the tumor microenvironment. Mechanistically, tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, and OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Furthermore, since OVM upregulates PD-L1 in DCs, the combination of anti-PD-L1 antibody with DC vaccine and OVM therapy can further enhance antitumor activity, offering a promising strategy for malignant tumor treatment.
In summary, this research suggests that oncolytic virus M1 (OVM) enhances the antitumor effect of DC vaccines by downregulating SIRPα-CD47 expression, relieving their dominant immune inhibitory effect, and promoting antitumor efficacy. This lays a theoretical foundation for OVM as a potent adjuvant for DC vaccines in clinical trials.
In 2010, the FDA approved the first DC-based autologous cancer vaccine, sipuleucel-T (Provenge), for treating prostate cancer. Clinically, DCs, as a novel immunotherapeutic tool, hold vast prospects for treating various tumors. To date, over 400 clinical studies worldwide have been conducted using DC-based vaccines to treat a variety of cancer types, including glioblastoma, acute myeloid leukemia, metastatic colorectal cancer, pancreatic cancer, high-risk melanoma, and more. Most clinical studies use monocyte-derived dendritic cells (Mo-DCs) for generating DC vaccines, benefiting from their high purity and ease of obtaining sufficient cells from peripheral blood.
Although DC vaccines can induce tumor-specific T cells, their efficacy remains limited primarily due to the immunosuppressive tumor microenvironment (TME) and insufficient tumor antigen (TAA) expression. On one hand, tumor cells reduce the expression of DC chemokines or cytokines, limiting DC survival, migration, and infiltration, and produce inhibitory factors that suppress DC differentiation and maturation. Moreover, immune checkpoints (e.g., PD-1, PD-L1, and TIM-3) expressed on DCs further weaken their function.
On the other hand, the low immunogenicity of tumors and low exposure of tumor-associated antigens (TAAs) make identifying ideal tumor-specific antigens more challenging, and these antigens are crucial for preparing DC vaccines. These factors limit the T-cell priming function of endogenous DCs in the tumor microenvironment (TME), potentially restricting the antitumor effect of DC vaccines. Thus, overcoming TME suppression and promoting TAA release are potential strategies to enhance the therapeutic effect of DC vaccines.
Oncolytic viral therapy is a strategy that selectively kills tumor cells using naturally occurring or genetically modified viruses without toxicity to normal cells. It has shown promising results in both clinical and preclinical studies. It has been reported that oncolytic viral therapy can also reverse tumor immune suppression, promote antigen release and presentation, generate antitumor immunity, and achieve significant therapeutic effects when used in combination with other cancer immunotherapies.
Therefore, oncolytic viruses may have the ability to alleviate the suppressive effect of TME and enhance the efficacy of DC vaccines. Additionally, oncolytic viruses can induce the type I interferon (IFN) pathway and promote the secretion of IFN-α/β, which is necessary for the transition of DC function and adaptive immune response.
M1 oncolytic vesicular stomatitis virus (OVM) is a novel naturally occurring oncolytic virus that targets tumor cells with overexpression of MXRA8 protein and defects in ZAP protein, without pathogenicity in non-human primates. Moreover, a series of studies have reported that OVM can significantly increase T-cell infiltration in the tumor microenvironment (TME), further enhancing the antitumor effect of immune checkpoint blockade therapy in various tumor-bearing mouse models. However, whether OVM has the potential to enhance the antitumor effect of DC vaccines has not been studied.
In this study, the research team found that the novel oncolytic virus OVM strongly enhances the antitumor effect of DC vaccines in various mouse tumor models.
The study further identifies the SIRPα/CD47 axis as a key immune inhibitory mechanism by which tumor cells suppress DC maturation and the efficacy of DC vaccines. Treatment with OVM downregulates SIRPα on the surface of DCs and CD47 on the surface of tumor cells, thereby alleviating the inhibition of DCs and restoring their ability to initiate T-cell responses. Additionally, OVM can induce an increase in PD-L1 expression in DCs, and blockade of PD-L1 with antibodies further enhances the antitumor efficacy of the combined therapy using OVM and DC vaccines.
These findings emphasize the critical role of oncolytic virus OVM as a dual inhibitor of the SIRPα/CD47 immune checkpoint axis, indicating the potential of oncolytic virus in combination with DC vaccines as a new cancer treatment approach in the future.