The team of Prof. Liufu Deng from School of Pharmacy, Shanghai Jiao Tong University (PhD students Lingling Wu and Xiaochuan Hong are the co-first authors) published a research paper in Science Immunology entitled: Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12.
The study explored the role of mitochondrial antiviral signaling proteins (MAVS) in tumor immunity, revealed their relationship with the immune response and potential therapeutic significance, and found that shutting down a portion of the innate immune system enhances antitumor activity. Specifically, in contrast to its role in the antiviral response, MAVS can support tumor growth and hinder antitumor therapy. In contrast, knockdown of MAVS in dendritic cells (DCs) promotes anti-tumor CD8+ T cell responses without affecting other immune cell populations. In addition, deletion of MAVS increased interleukin-12 (IL-12) expression in dendritic cells in the tumor microenvironment and in draining lymph nodes, and the deletion also appeared to affect the transport of tumor antigens to the draining lymph nodes rather than antigen presentation.
These findings suggest that inhibition of the MAVS signaling pathway in dendritic cells (DCs) enhances anti-tumor immunity and improves current cancer therapies (radiotherapy, immune checkpoint blockade therapy).
Mitochondrial antiviral signaling protein (MAVS)-mediated cytoplasmic RNA perception plays an important role in immune surveillance against pathogens and tumors. Following viral RNA recognition, RIG-I and MDA5 activate their shared junction protein MAVS, which subsequently induces the production of type I interferon (IFN-I) and other pro-inflammatory cytokines.
The endogenous MAVS pathway in tumor cells mediates a viral mimetic program that induces IFN-I signaling, enhances anti-tumor immune responses, and ultimately increases susceptibility to immune checkpoint blockade. This enhanced tumor immunogenicity has been observed in several different epigenetic therapies. In addition, several recent studies have identified additional functions of MAVS that are independent of the IFN-I response, for example, MAVS maintains p53 protein stability by preventing the formation of the p53-MDM2 complex in response to DNA damage and promotes homeostasis of lymphocytes within the intestinal epithelium via the interferon regulatory factor 1 (IRF1)-interleukin 15 (IL-15) axis.
Although the MAVS signaling cascade is considered a potential therapeutic target to reactivate the T-cell inflammatory tumor microenvironment, how host MAVS modulates the tumor immune response remains unclear.
In this study, the team found that the MAVS pathway supports tumor growth and impairs anti-tumor immunity through a genetically engineered mouse model, whereas knockdown of MAVS in dendritic cells (DCs) promotes anti-tumor responses in CD8+ T cells.
Specifically, knockdown of MAVS in dendritic cells enhanced CD8+ T cells in an IFN-I-independent but IL-12-dependent manner. Mechanistically, deletion of the RIG-I/MAVS cascade activated the non-classical NF-κB pathway, which in turn induced IL-12 production in dendritic cells, thereby promoting cross-reactivity between CD8+ T cells and dendritic cells. In addition, tumor mouse models with knockout of MAVS were more sensitive to anti-PD-L1 immune checkpoint blockade therapy and radiotherapy and promoted maintenance of effector CD8+ T cells.
These results suggest that interfering with the MAVS pathway in dendritic cells may be a promising cancer therapeutic strategy to enhance anti-tumor immune responses, especially in combination with treatments such as radiotherapy and immune checkpoint blockade therapy.
