Autophagy, Inflammation, and Immunity: A Troika Governing Cancer and Its Treatment

Abstract

Autophagy, a cellular waste disposal process, has well-established tumor-suppressive properties. New studies indicate that, in addition to its cell-autonomous anti-tumorigenic functions, autophagy inhibits cancer development by orchestrating inflammation and immunity. While attenuating tumor-promoting inflammation, autophagy enhances the processing and presentation of tumor antigens and thereby stimulates anti-tumor immunity. Although cancer cells can escape immunosurveillance by tuning down autophagy, certain chemotherapeutic agents with immunogenic properties may enhance anti-tumor immunity by inducing autophagic cell death. Understanding the intricate and complex relationships within this troika and how they are affected by autophagy enhancing drugs should improve the efficacy of cancer immunotherapy.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Figure 1. Speculative Models of How Cancer Risk Factors Compromise Autophagy

Cancer risk factors, including obesity, aging, alcohol abuse, chronic inflammation and infection interfere with either the initiation or termination of autophagy to promote cancer development. ULK, unc51-like kinase; PI3KC, class III phosphatidylinositol (PI) 3’ kinase; ATG, autophagy related gene; AMPK AMP-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; ER, endoplasmic reticulum; IL-1β, interleukin 1β; ROS, reactive oxygen species; HCV, hepatitis C virus; HBV, hepatitis B virus; EBV, Epstein-Barr virus; KSHV, Kaposi’s sarcoma-Assocaited Herpesvirus; cFLIP, viral FLICE inhibitory protein; vBcl-2, viral B-cell lymphoma 2; EBNA1, EBV nuclear antigen 1; VacA, vacuolating cytotoxin A; HBx, HBV×protein; H. pylori, Helicobacter pylori. Mechanistic details are provided in the main text.

Figure 2. The “Autophagy-Inflammation-Immunity” (AII) troika in Cancer

Overview of the cancer governing “AII” troika and how its function is modified by certain cancer-associated processes. MHC I, major histocompatibility complex I; ICD, immunogenic cell death; DAMP, damage-associated molecular patterns; NLRP3, nod-like receptor pyrin domain containing protein 3.

Figure 3. Mitophagy/Autophagy Dials Down Inflammation

Stimulation of macrophages with DAMP (e.g. ATP and uric acid), carcinogenic particles (asbestos and silica microfibers/crystals) or PAMP (e.g. bacterial toxins) results in mitochondrial damage that is characterized by loss of mitochondrial membrane potential and subsequent release of mtDNA and mtROS. These mitochondrial signals in turn activate the NLRP3 inflammasome to induce IL-1β and IL-18 secretion. Loss of mitochondrial membrane potential (ψm) activates PINK1, a mitochondrial protein kinase that phosphorylates ubiquitin chains attached to mitochondrial outer membrane proteins. Phosphorylated ubiquitin interacts with and activates Parkin, an E3 ubiquitin ligase that further ubiquitinates mitochondrial outer membrane proteins. Ubiquitin-tagged mitochondria are recognized by the UBA domain of p62, whose expression is induced upon NF-κB activation. p62 also binds to LC3 and targets ubiquitinated mitochondria to autophagosomal clearance. By eliminating signal-emitting mitochondria, macrophage limits the extent of NLRP3-inflammasome activation. MSU, monosodium urate crystal; PINK1, PTEN-induced putative kinase 1; LC3, microtubule-associated protein 1A/1B light chain 3; NF-κB, nuclear factor-kappa B; UBA, ubiquitin association domain.

Figure 4. Autophagy Fuels Immunogenic Cell Death

Overview of the roles of autophagy in ICD. Ionizing radiation, oncolytic viruses and certain chemotherapeutic agents induce autophagy-dependent release of DAMP and tumor antigens by cancer cells. DAMP lead to maturation and advanced activation of APC, which after engulfing tumor antigens, use autophagy to process antigens and cross-present them to T cells, leading to activation of CTL survival and maturation are also stimulated by autophagy. CTL activation can be limited upon engagement of the inhibitory receptors CTLA-4 and PD-1 by ligands that are present within the tumor bed. Immune checkpoints inhibitors overcome this inhibition and promote effective CTL-mediated tumor eradication, especially when combined with ICD inducers. HSP70/90, heat shock protein 70/90; HMGB1, high mobility group box 1 protein; RAGE, receptor for advanced glycation endproducts; P2X7, purinergic receptor P2X, ligand-gated ion channel 7; TLR2/4, toll-like receptor 2/4; CTL, cytotoxic T-lymphocytes; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1.