Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer

Abstract

Oncolytic virotherapy has recently emerged as a promising strategy for inducing tumor-specific cell death. Adenoviruses are widely and frequently used in oncolytic virotherapy. The mechanism of oncolytic adenovirus-mediated tumor suppression involves virus-induced activation of the autophagic machinery in tumor cells. Autophagy is a cytoprotective process that produces energy via lysosomal degradation of intracellular components as a physiologic response to various stresses, including hypoxia, nutrient deprivation, and disruption of growth signaling. However, infection with oncolytic adenoviruses induces autophagy and subsequent death of tumor cells rather than enhancing their survival. In this review, we summarize the beneficial role of autophagy in oncolytic adenoviral therapy, including the roles of infection, replication, and cell lysis. Numerous factors are involved in the promotion and inhibition of oncolytic adenovirus-mediated autophagy. Furthermore, recent evidence has shown that oncolytic adenoviruses induce autophagy-related immunogenic cell death (ICD), which enhances the antitumor immune response by inducing the activation of danger signal molecules and thus represents a novel cancer immunotherapy. Understanding the precise role of oncolytic adenovirus-induced autophagy and ICD could enhance the therapeutic potential of oncolytic adenoviral therapy for treating various cancers.

Keywords: autophagy; immunogenic cell death; oncolytic adenovirus.

Figure 1

Life cycle of oncolytic adenoviruses and induction of autophagy in infected tumor cells. Oncolytic adenoviruses are internalized into the cytoplasm through binding to adenovirus receptors and subsequent endosomal encapsulation. Virus DNA is transferred into the nucleus, resulting in the replication of oncolytic adenoviruses. During viral replication, adenoviral DNA-derived E1A, E1B, and E4 accumulate in the cytoplasm. Expression of Atg5 is upregulated in response to viral replication. After the Atg5–Atg12 complex binds to the isolation membrane, LC3-II, p62, and intracellular components cooperatively accumulate at the isolation membrane, resulting in formation of an autophagosome. The autophagosome fuses with the lysosome to become an autolysosome, in which p62 and cytoplasmic components are degraded under acidic conditions. FADD-induced enhancement of autophagy contributes to viral replication, cell lysis, and virus spread.

Figure 2

Factors that promote or inhibit oncolytic adenovirus-mediated autophagy. Factors that promote or inhibit oncolytic adenovirus-mediated autophagy are shown. HDACi, histone deacetylase inhibitor; JNK, c-Jun N-terminal kinase; ULK1, unc-51-like autophagy-activating kinase 1; TMZ, temzolomide; miRNA, microRNA; mTOR, mammalian target of rapamycin; CDV, cidofovir; DRAM, damage-regulated autophagy modulator; TAM, tamoxifen; EGFR, epidermal growth factor receptor; 3-MA, 3-methyladenine; BA1, bafilomycin A1.

Figure 3

Role of oncolytic adenovirus-induced immunogenic cell death in antitumor immunity. Oncolytic adenovirus-induced autophagy contributes to the induction of immunogenic cell death, which causes the release of danger signal molecules, such as ATP, HMGB1, uric acid, and tumor antigens.