Abstract
Oncolytic viruses have the potential to induce immunogenic cell death (ICD) that may provoke potent and long-lasting anti-cancer immunity. Here we aimed to characterize the ICD-inducing ability of wild-type Adenovirus (Ad), Semliki Forest virus (SFV) and Vaccinia virus (VV). We did so by investigating the cell death and immune-activating properties of virus-killed tumor cells. Ad-infection of tumor cells primarily activates autophagy, but also activate events of necroptotic and pyroptotic cell death. SFV infection on the other hand primarily activates immunogenic apoptosis while VV activates necroptosis. All viruses mediated lysis of tumor cells leading to the release of danger-associated molecular patterns, triggering of phagocytosis and maturation of dendritic cells (DCs). However, only SFV-infected tumor cells triggered significant T helper type 1 (Th1)-cytokine release by DCs and induced antigen-specific T-cell activation. Our results elucidate cell death processes activated upon Ad, SFV, and VV infection and their potential to induce T cell-mediated anti-tumor immune responses. This knowledge provides important insight for the choice and design of therapeutically successful virus-based immunotherapies.
Highlights
Many human viruses are being evaluated for their abilities to selectively infect, replicate in and kill cancer cells and be used as therapeutic oncolytic viruses (OVs) for the treatment of various human malignancies
We investigated which of the most common cell death pathways were activated upon infection of HOS and A549 tumor cells by wild-type Adenovirus (Ad) serotype 5, Semliki Forest virus (SFV) strain SFV4 and Vaccinia virus (VV) Western Reserve strain
Densitometric analysis of fold change in Phosphorylated RIP3 (p-RIP3) post Ad-infection in (h) HOS and (i) A549 compared to un-infected control (n = 3). (j) HOS and A549 cells cultured on glass slides were infected with Ad (MOI = 10) for 48 h and phosphorylated mixed-lineage kinase domain-like (MLKL) (p-MLKL) was detected by antibody staining
Summary
Many human viruses are being evaluated for their abilities to selectively infect, replicate in and kill cancer cells and be used as therapeutic oncolytic viruses (OVs) for the treatment of various human malignancies. Inducers of ICD are characterized by their ability to stimulate the release of damage-associated molecular patterns (DAMPs) from dying host cells, such as extracellular ATP (“find-me” signal), cell surface exposure of Calreticulin (CRT) (“eatme” signal to antigen-presenting cells), and release of high mobility group box 1 protein (HMGB1) (activation signal for immune cells). They serve as strong immune stimulants and ICD is regarded as a keystone of anti-tumor immunity[5,6].
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