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.

Healing after death: antitumor immunity induced by oncolytic adenoviral therapy

“…6 Although not completely expected, our observations are in agreement with previous reports demonstrating that expression of DAMPs by cancer cells is observed in the course of infection by different types of viruses, including measles and Coxsackie B viruses. 1 We and others have also reported that adenoviruses induce potent autophagy in host cells. 4,7 Although the roles of autophagy during adenoviral infection have yet to be completely defined, it is clear that the autophagic process is one of the main pathways by which viral antigens are processed.…”

“…1 In the current paradigm of oncolytic virotherapy, the development of an antitumor immune response is responsible for clinical success. In this model, the virus overcomes or reverses the characteristic immune evasion of solid tumors 2 and facilitates specific recognition of tumorassociated antigens (TAAs) by the host immune system.…”

“…Thus, the intratumoral necrosis (local effect) induced by the oncolysis serves as a mechanism for activation of the innate and adaptive immune responses that will eventually be responsible for the elimination of distant invasive cells, including metastases (systemic effect). 1 However, the immunodominance hypothesis seems to argue against the possibility of an adenovirus-mediated triggering of antitumor immunity. 3 The immunodominance model proposes that an immune response is directed against a few epitopes (dominant antigens) of all the many epitopes produced during an infection.…”

“…Immunogenic cell death is characterized by the pre-apoptotic exposure of calreticulin and is thought to regulate the immune response to tumor cells observed during anticancer therapeutic strategies, 9 including treatment with oncolytic adenoviruses. 1 Thus, measles and Coxsackie B viruses have been shown to induce immune-stimulatory cell death in melanoma and lung cancer.…”

Fighting Cancer with Mathematics and Viruses

“…More importantly, oncolysis represents a form of immunogenic cell death, resulting in the release of potent immune-stimulatory molecules, including cytokines, pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs, respectively) and tumor-associated antigens (reviewed in [84]). This can induce recruitment of cells of both the innate and the adaptive immune system, potentially leading to systemic anti-tumor immunity.…”