Immunotherapy has garnered significant attention due to its potential in achieving long-term control of tumor progression and extending the survival of patients in cancer treatment. Dendritic cells (DCs), known as the most potent specialized antigen-presenting cells in the body, play a crucial role in shaping adaptive anti-tumor responses. However, despite some breakthroughs in recent years in utilizing DCs as therapeutic vaccines, many patients have not experienced significant clinical benefits. This is attributed to tumor cells restricting the survival, migration, and infiltration of DCs through various mechanisms, including cytokines and immune checkpoints, while also inhibiting their differentiation and maturation, thereby impeding their ability to effectively initiate anti-tumor T-cell responses. Consequently, overcoming the immune-suppressive tumor microenvironment has become a critical challenge in enhancing the clinical efficacy of DC vaccines.
Oncolytic viruses represent a novel therapeutic strategy that employs naturally occurring or genetically modified viruses to selectively target tumor cells while sparing normal cells. These viruses, acting as pathogens, can activate the body’s antiviral response, modulate systemic immunity, and improve the tumor microenvironment. The induction of type I interferons (IFN), anti-viral cytokines, by oncolytic viruses is crucial for the functionality and survival of DCs. In this context, oncolytic viruses possess the potential to disrupt the tumor microenvironment’s suppression of DC vaccines, stimulate the maturation of DC vaccines, and thereby enhance the performance of DC vaccines in clinical applications.
The team led by Professor Guangmei Yan and Professor Yuan Lin from Sun Yat-sen University School of Medicine published a study titled “Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine” in Cell Reports Medicine. The research revealed that tumor cells inhibit the maturation of DCs and weaken the anti-tumor activity of DC vaccines through contact-dependent signaling involving Signal Regulatory Protein α (SIRPα)-CD47 immune checkpoint pathway. However, the oncolytic virus M1 (OVM) can downregulate SIRPα in DCs and CD47 in tumor cells, reversing the tumor’s inhibitory effects on DC vaccines, thereby improving the therapeutic efficacy of DC vaccines in various tumor-bearing mouse models. Furthermore, this effect can be further enhanced by PD-L1 blockade.
This study elucidates the critical role of SIRPα-CD47 in DC functionality and the feasibility of these molecules as potential targets to enhance DC vaccine efficacy. It also confirms the novel function of oncolytic virus M1 in reversing tumor immune suppression by reducing the expression of immune checkpoints, offering a potential adjuvant for enhancing the clinical application of DC vaccines.
Reference
1. Dan, Jia, et al. “Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine.” Cell Reports Medicine 4.10 (2023).