Browsing by Subject "epigenetics"

Immune checkpoint inhibitor (ICI) therapy aims to enhance the endogenous immune response against tumour cells, and it has become a potent treatment option for various types of cancers. Despite the promise of ICIs, most patients do not respond to the treatment. The primary limitation of ICI therapy is the immunosuppressive tumour microenvironment (TME), which is characterised by the lack of tumour- infiltrating cytotoxic T cells (CTLs) and the presence of immunosuppressive cells, such as tumour- associated macrophages (TAMs). A promising immunotherapeutic strategy that can promote antitumor immunity is oncolytic virus (OV) therapy. OVs can selectively replicate in and kill cancer cells, leading to the release of immunostimulatory molecules. These molecules can induce local inflammation and prime and recruit CTLs to the tumour site. In addition, OVs can also be used as a delivery platform for immunostimulatory transgenes that can further enhance the activation of anti-tumour immune response and help to overcome the immunosuppressive TME. Another strategy used to support anti-tumour immune responses and overcome immunosuppressive TME is epigenetic therapy. Epigenetic therapy can reprogram both cancer and immune cells towards a less immunosuppressive phenotype, thus helping to overcome the limitation of immune checkpoint therapy. The aim of this study was to generate a novel oncolytic adenovirus armed with epigenetic modifying transgene (EpiCRAd) to overcome the immunosuppressive TME and enhance the anti-tumour immune response. We tested its efficacy and immunogenicity in vitro and in vivo using a murine triple-negative breast cancer model. We demonstrated that EpiCRAd was able to modulate the epigenome of cancer cells without affecting viruses’ infectivity. Upon examining the potential effect of EpiCRAd on cancer cells, we observed that epigenetic regulation did not notably influence the expression of MHC class I and PD- L1 proteins, both of which play a role in the immune evasion mechanism of tumour cells. In addition, the in vivo experiments show that EpiCRAd controls tumour growth the best, especially together with an immune checkpoint inhibitor, suggesting that the virus was able to create an immune microenvironment more favourable for anti-tumour response. Interestingly, the TAM infiltration in the TME seems to reduce after treatment with EpiCRAd. Overall, the combination of epigenetic therapy with oncolytic virotherapy has shown promising results in converting immunotherapy-resistant tumours into immunotherapy-responsive tumours. Our findings provide valuable insights into the effect of EpiCRAd on cancer and immune cells. This study encourages exploring the use of epigenetic cancer remodelling and oncolytic viruses for cancer immunotherapy.