Autophagy in Tumor Immunity and Viral-Based Immunotherapeutic Approaches in Cancer

Abstract

Autophagy is a fundamental catabolic process essential for the maintenance of cellular and tissue homeostasis, as well as directly contributing to the control of invading pathogens. Unsurprisingly, this process becomes critical in supporting cellular dysregulation that occurs in cancer, particularly the tumor microenvironments and their immune cell infiltration, ultimately playing a role in responses to cancer therapies. Therefore, understanding “cancer autophagy” could help turn this cellular waste-management service into a powerful ally for specific therapeutics. For instance, numerous regulatory mechanisms of the autophagic machinery can contribute to the anti-tumor properties of oncolytic viruses (OVs), which comprise a diverse class of replication-competent viruses with potential as cancer immunotherapeutics. In that context, autophagy can either: promote OV anti-tumor effects by enhancing infectivity and replication, mediating oncolysis, and inducing autophagic and immunogenic cell death; or reduce OV cytotoxicity by providing survival cues to tumor cells. These properties make the catabolic process of autophagy an attractive target for therapeutic combinations looking to enhance the efficacy of OVs. In this article, we review the complicated role of autophagy in cancer initiation and development, its effect on modulating OVs and immunity, and we discuss recent progress and opportunities/challenges in targeting autophagy to enhance oncolytic viral immunotherapy.

Regulation of autophagy fires up the cold tumor microenvironment to improve cancer immunotherapy

“…It then stimulates the expression of numerous genes involved in establishing immunosuppressive TME ( 22 ). Activated HIF-1 signaling attenuates MHC-I antigen presentation and hampers the infiltration and cytotoxic functions of the effector T cells and NK cells ( 22 , 23 ). And, enhanced HIF-1 promotes the development and recruitment of immunosuppressive cells including M2-type macrophages, MDSC, and Treg ( 22 , 23 ).…”

“…Activated HIF-1 signaling attenuates MHC-I antigen presentation and hampers the infiltration and cytotoxic functions of the effector T cells and NK cells ( 22 , 23 ). And, enhanced HIF-1 promotes the development and recruitment of immunosuppressive cells including M2-type macrophages, MDSC, and Treg ( 22 , 23 ). Furthermore, HIF-1-mediated elevated expression of PD-L1 and CD47 contributes to the exhaustion of CTL and inactivation of phagocytosis ( 22 , 23 ).…”

“…And, enhanced HIF-1 promotes the development and recruitment of immunosuppressive cells including M2-type macrophages, MDSC, and Treg ( 22 , 23 ). Furthermore, HIF-1-mediated elevated expression of PD-L1 and CD47 contributes to the exhaustion of CTL and inactivation of phagocytosis ( 22 , 23 ). Negative regulatory genes of the anti-tumor immune were found to be largely elevated in hypoxia TME, associated with the malignant phenotype of the tumors and poor patient prognosis ( 24 ).…”

Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy

“…For example, induction of autophagy enhanced replication of oncolytic Adenoviruses and NDV [ 56 , 57 ]. Autophagy also enhanced antitumor effects via oncolysis, autophagic cell death, and ICD [ 58 , 59 , 60 , 61 ].…”

Regulation and therapeutic applications of autophagy in cancer

“…AMP-activated protein kinase (AMPK) and mammalian rapamycin complex 1 (mTORC1) control ULK1 in a positive and a negative fashion, respectively. In turn, regulatory elements such as RAG, SLC38A9, and KICSTOR control the activation of mTORC1 [10]. During nutrient-rich circumstances, active mTORC1 suppresses the ULK1 complex by phosphorylating ULK1/2 or ATG13, hence blocking autophagy induction.…”