Autophagy in the Immune System and in Malignancy
Introduction
Autophagy has a complex dual role in cell survival and cell death and has been rigorously studied in relation to the immune system and in cancer, particularly in the role that the immune system plays in the removal of malignant cells. Autophagy can promote or inhibit tumor development depending on the cell type and tumor stage. How autophagy regulates the immune system to attack malignant cells is therefore of interest (Jiang et al. 2019). Many anti-cancer therapies attempt to modulate autophagy, for example using autophagy related gene (ATG) inducers/inhibitors or preventing autophagosome-lysosome fusion, with the aim to enhance the immune response and anti-tumor effects of immunotherapies (Cuomo et al. 2019).
There have been many recent studies on autophagy, demonstrating the importance of this process in modulating immune cells of both the innate and adaptive immune system. A brief summary is outlined below.
Innate Immunity
In innate immunity, autophagy is up-regulated downstream of pattern recognition receptors by activation of innate immune receptors such as Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) - like receptors (NLRs), where it facilitates a number of effector responses. These include natural killer T (NKT) cell activation, cytokine production in neutrophils, phagocytosis, and differentiation of neutrophils, NK cells, and macrophages (Jiang et al. 2019), (Germic et al. 2019a), (Germic et al. 2019b). Autophagy has also been shown to modulate NK cell migration into tumor tissue, where targeting autophagy increases NK infiltration into melanoma tissues and improves patient survival (Mgrdtichian T et al. 2017).
Adaptive Immunity
In adaptive immunity, autophagy has a role in degrading intracellular bacteria, parasites, and viruses, providing a source of antigens for loading onto MHC class II molecules. Autophagy may also be important in dendritic cells for cross-priming to CD8+ T cells. Viral nucleic acids are transferred by autophagy from the cytoplasm to intracellular compartments containing Toll-like receptor 7 which signals the production of type 1 interferon (Jiang et al. 2019). Autophagy is essential for T cell homeostasis, survival, activation, differentiation, and metabolic regulation in T cells. Both CD4+ and CD8+ T cells upregulate autophagy in response to T cell receptor (TCR) engagement which ultimately results in proliferation, differentiation, and cytokine production (Macian 2019). Autophagic activity declines in aged T cells which causes defects in TCR signaling and contributes to immune senescence (Zhang et al. 2016). Autophagy is also crucial to the survival, function, and homeostasis of B cells and B cell progenitors. This is particularly important in secreting plasma cells which need to maintain their endoplasmic reticulum, remodel their proteome, and secrete large amounts of correctly folded antibodies (Cui et al. 2019).
The Role of Autophagy in Malignancy
A link between autophagy and cancer was first identified in 1999 when an autophagy gene, Beclin 1, was discovered to be deleted in breast tumor cells (Liang et al. 1999). At present the role of autophagy in cancer is far from clear, but is considered to be a double-edged sword. In the early stages of cancer, autophagy is generally beneficial to the host and protects against tumorigenesis, however once a tumor is established, it contributes to cancer progression (Jiang et al. 2019).
Autophagy in Early Malignancy
In the early stages of cancer, autophagy acts as a tumor suppressive mechanism. It helps maintain genome stability and cell injury by removing damaged proteins and mitochondria, reducing damage by reactive oxygen species (ROS), and inhibiting inflammation, which are features of early cancer development. This maintains cell quality, preventing tumor initiation and proliferation. Since the initial identification of a link between Beclin 1 and breast cancer, other autophagy genes have been associated with tumorigenesis, including ATG5 and ATG12 mutations (Li et al. 2020).
Autophagy in Established Malignancy
In established cancer, autophagy can act to progress tumors to late stage and promote cancer metastasis. In the majority of reports, autophagy enhances the survival of cells in established tumors by removing toxic oxygen radicals and damaged proteins, and allows cells to grow in stress conditions such as hypoxia and nutrient deprivation. Different tumor cells have a range of reliance on autophagy; in vitro studies have shown that responses to autophagy inhibition in tumor cells range from no effect, slower growth, or causing the tumor cells to die (Towers et al. 2020).
Autophagy in Treatment for Malignancy
During cancer treatments (radiation therapy, chemotherapy and immunotherapies), malignant cells upregulate autophagy further as a mechanism to prevent their death (Li et al. 2019). It is therefore thought that using autophagy inhibitors for the treatment of cancers that rely on autophagy could enhance and increase the effectiveness of conventional therapies, especially when given in combination. Many such clinical trials have taken place or are in progress (for more information, visit ClinicalTrials.gov). The most common autophagy inhibitors used in clinical trials are chloroquine (CQ) and hydroxychloroquine (HCQ), as both of these have been approved for use in other indications. They work by inhibiting the autophagosome-lysosome fusion in the autophagy pathway. They have shown positive efficacy and have demonstrated a good safety profile in combination with cytotoxic chemotherapies (Jiang et al. 2019), (Pérez-Hernández et al. 2019). However, none are currently approved for use in a clinical setting as an anti-cancer therapy. This is in part due to clinical trials highlighting the need for a reliable biomarker for autophagy detection to help determine efficacy.
The dual role of autophagy in cancer means that it will be vital to identify patients with cancers susceptible to autophagy inhibition/induction, with treatments most likely to be administered in combination with conventional cancer treatments (Pérez-Hernández et al. 2019).
Summary
Both the innate and adaptive immune systems are critical for health, fighting pathogens, and removing malignant cells. Autophagy is upregulated downstream of PRRs in innate immunity cells and is crucial for cell homeostasis, survival, and development of adaptive immune cells. Autophagy maintains normal physiological function and allows cells to respond correctly to a threat. It has been shown to be helpful in preventing cancer progression but also promotes survival of established cancers. Modulation of both the immune response and autophagy could be crucial in finding new treatments, and improving current treatments when combined with chemotherapy and radiotherapy.
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