Oncolytic virotherapy and immunogenic cancer cell death: sharpening the sword for improved cancer treatment strategies

Abstract

Oncolytic viruses are novel immunotherapeutics with increasingly promising outcomes in cancer patient clinical trials. Preclinical and clinical studies have uncovered the importance of virus-induced activation of antitumor immune responses for optimal therapeutic efficacy. Recently, several classes of chemotherapeutics have been shown to cause immunogenic cancer cell death characterized by the release of immunomodulatory molecules that activate antigen-presenting cells and thus trigger the induction of more potent anticancer adaptive immune responses. In preclinical models, several oncolytic viruses induce immunogenic cell death, which is associated with increased cross-priming of tumor-associated antigens. In this review, we discuss the recent advances in immunogenic cancer cell death as induced by chemotherapeutic treatments, including the roles of relevant danger-associated molecular patterns and signaling pathways, and highlighting the significance of the endoplasmic reticulum (ER) stress response. As virtually all viruses modulate both ER stress and cell death responses, we provide perspectives on future research directions that can be explored to optimize oncolytic viruses, alone or in combination with targeted drug therapies, as potent immunogenic cancer cell death-inducing agents. We propose that such optimized virus-drug synergistic strategies will improve the therapeutic outcomes for many currently intractable cancers.

Figure 1

Conventional immunogenic cell death (ICD) inducers (chemotherapeutics and UV radiation) and oncolytic viruses induce a similar danger response, leading to anticancer immunity. Immunogenic cell death induced by UV radiation and specific chemotherapeutic agents results in reactive oxygen species (ROS) production and an endoplasmic reticulum (ER) stress response (left side of figure). Active infection of tumor cells by oncolytic viruses overwhelms the cellular machinery, resulting in ER stress and tumor cell death (right side of figure). During these sequences of events, tumor cells express calreticulin (CRT) on the cell surface that attracts antigen-presenting cells (APCs). In addition, dying cells release immunomodulatory molecules such as high-mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) into the extracellular tumor microenvironment, leading to potent antigen presentation. APCs that take up tumor-associated antigens migrate to the lymph nodes to present antigens to T cells for establishment of anticancer immunity. In addition to danger-associated molecular patterns (DAMPs), oncolytic virus infected tumor cells release pathogen-associated molecular patterns (PAMPs) (foreign viral proteins and viral dsRNA) that are potent activators of innate immune cells to secrete cytokines, such as the type I IFN. These cytokines help orchestrate the anticancer adaptive immune response.