Immunogenic cell death: The cornerstone of oncolytic viro-immunotherapy

Abstract

According to the World Health Organization, cancer is one of the leading global health concerns, causing nearly 10 million deaths in 2020. While classical chemotherapeutics produce strong cytotoxicity on cancer cells, they carry limitations of drug resistance and off-target effects and sometimes fail to elicit adequate antitumor protection against tumor relapse. Additionally, most cancer cells have developed various ways to escape immune surveillance. Nevertheless, novel anticancer strategies such as oncolytic viro-immunotherapy can trigger immunogenic cell death (ICD), which can quickly grasp the attention of the host defense machinery, resulting in an ensuing antitumor immune response. Specifically, oncolytic viruses (OVs) can infect and destroy targeted cancer cells and stimulate the immune system by exposing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to promote inflammatory reactions, and concomitantly prime and induce antitumor immunity by the release of neoantigens from the damaged cancer cells. Thus, OVs can serve as a novel system to sensitize tumor cells for promising immunotherapies. This review discusses the concept of ICD in cancer, centralizing ICD-associated danger signals and their consequence in antitumor responses and ICD induced by OVs. We also shed light on the potential strategies to enhance the immunogenicity of OVs, including the use of genetically modified OVs and their combination with ICD-enhancing agents, which are helpful as forthcoming anticancer regimens.

Keywords: anticancer immunotherapy; combination therapy; damage-associated molecular patterns (DAMPs); immunogenic cell death (ICD); oncolytic virus (OV); pathogen-associated molecular patterns (PAMPs); viral engineering.

Figure 1

Illustration of the mechanism of immunogenic cell death and the subsequent activation of the antitumor immune response. When exposed to different immunogenic cell death (ICD) inducers, including OVs, cancer cells are under extreme ER stress and undergo ICD. Dying cancer cells express various damage-associated molecular patterns (DAMPs), including the release of high mobility group box 1 (HMGB1) from the nucleus, translocation and cell surface exposure of calreticulin (ecto-CRT) and heat shock proteins HSP70/90, and extracellular secretion of ATP, Annexin A1 (AXNA1), cytokines, chemokines, and nucleic acids. Exposure to DAMPs serves as a "find me" signal which recruits immature DC to TME and induces the maturation of DC. Ecto-CRT provides a pro-phagocytic signal that promotes the phagocytosis of antigens by DC. In addition, HMGB1 and HSP70/90 assist in promoting the processing of phagocytic cargo by binding to toll-like receptors (TLRs), thereby escalating antigen engulfment, processing, and presentation to T cells to mediate tumor-specific immune response and protective immunological memory. Created with BioRender.com.

Figure 2

Illustration of the immunogenic cell death related pathways induced by natural OVs. Several natural oncolytic viruses (OVs), including coxsackievirus A, B (CVA, CVB), Newcastle disease virus (NDV), adenovirus (Ad), semliki forest virus (SFV), measles virus (MV), herpes simplex virus (HSV) and poxviruses, such as vaccinia virus (VACV) and parapoxvirus (ORFV) can induce a distinct mode of immunogenic cell death (ICD). For example, CVA, CVB, MV, ORFV, and SFV induce immunogenic apoptosis, and VACV induces necroptosis. While some OVs, such as HSV, NDV, and Ad, induce multimodal cell death, mediating chronic exposure of DAMPs in dying cancer cells. During this phase, the dying tumor cells exposing multiple damage-associated molecular patterns (DAMPs) recruit innate immune responders, thus connecting the bridge between TME and host innate immune machinery, eliciting a potent antitumor immune response. Created with BioRender.com.