Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

Abstract

Macroautophagy (hereafter referred to as autophagy) is a housekeeping process constitutively executed at basal level in all cells to promote cellular homeostasis by regulating organelle and protein turnover. However, autophagy deregulation caused by several stress factors, such as hypoxia, is prevalent in many cancers. It is now well established that autophagy can act as tumor suppressor or tumor promoter depending on tumor type, stage, and genetic context. In developed tumors, autophagy promotes the survival of cancer cells and therefore operates as a cell resistance mechanism. Emerging evidence point to the prominent role of autophagy in disabling the antitumor immune response by multiple overlapping mechanisms leading to tumor escape from immune cell attack mediated by both natural killer cells and cytotoxic T-lymphocytes. Such a role has inspired significant interest in applying anti-autophagy therapies as an entirely new approach to overcome tumor escape from immune surveillance, which constitutes so far a major challenge in developing more effective cancer immunotherapies. In this review, we will summarize recent reports describing how tumor cells, by activating autophagy, manage to hijack the immune system. In particular, we will focus on the emerging role of hypoxia-induced autophagy in shaping the antitumor immune response and in allowing tumor cells to outmaneuver an effective immune response and escape immunosurveillance. In keeping with this, we strongly believe that autophagy represents an attractive future therapeutic target to develop innovative and effective cancer immunotherapeutic approaches.

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…In antigen-presenting cells, autophagy promotes antigen presentation by MHC. 34 This phenotype has often been observed in solid neoplasms and generally leads to more aggressive treatment-resistant tumor phenotypes. 64 MHC-I-driven presentation, which tends to be promoted by CQ, exposes cancer-derived neoantigens to the immune system.…”

“…In antigen-presenting cells, autophagy promotes antigen presentation by MHC. 34 Lysosomal acidification in distinct phases of the pathways that lead to antigen presentation is needed and this need depends heavily on the nature of the antigen. 64 MHC-I-driven presentation, which tends to be promoted by CQ, exposes cancer-derived neoantigens to the immune system.…”

“…Autophagy, especially under hypoxia, permits activation of transcription factor STAT3, leading to the expression and secretion of cytokines such as IL-10, and a number of other factors with immunosuppressive effects that help cancer cells escape multiple components of the immune system. 34 This phenotype has often been observed in solid neoplasms and generally leads to more aggressive treatment-resistant tumor phenotypes. 9 Consequently, blocking the hypoxia-induced autophagy in tumors restored cytotoxic T-cell activity and promoted regression of melanoma xenografts in mice.…”

“…30 The tumor microenvironment is often acidic, in contrast to normal tissue that, at least under homeostatic conditions, is mostly slightly alkaline. 34 Analysis of related data shows that a substantial part of the effects of CQ is due to its interference with cellular metabolism, gene regulation, and mechanisms that trigger innate immunity including signaling pathways through Toll-like receptors (TLR) and tumor necrosis factor-a (see Supplementary material, Appendix S1). 32 Compared with the normal cells, cancer cells use more glucose to sustain a high proliferation rate with an increase in the conversion of glucose to lactic acid with the release of protons, causing a decrease in the pH level that leads to elevated acidity.…”

“…33 This has been the subject of various studies, from which evidence is emerging that CQ can significantly strengthen the antineoplastic immune response, at least under certain conditions. 34 Analysis of related data shows that a substantial part of the effects of CQ is due to its interference with cellular metabolism, gene regulation, and mechanisms that trigger innate immunity including signaling pathways through Toll-like receptors (TLR) and tumor necrosis factor-a (see Supplementary material, Appendix S1). 35,36 It is important to note that cell stress from antineoplastic treatment and CQs can activate some transcription factors, which may reprogram the cells and thereby enable tumor cells to escape from cell death induced by drug treatment or from the immune system.…”