Autophagy, the innate immune response and cancer

Abstract

Autophagy is a cellular degradation and recycling system, which can interact with components of innate immune signalling pathways to enhance pathogen clearance, in both immune and nonimmune cells. Whilst this interaction is often beneficial for pathogen clearance, it can have varying outcomes in regard to tumorigenesis. Autophagy and the innate immune response can have both pro- and antitumorigenic effects at different stages of tumorigenesis due to the plastic nature of the tumour microenvironment (TME). Although both of these components have been studied in isolation as potential therapeutic targets, there has been less research concerning the interaction between autophagy and the innate immune response within the TME. As the innate immune response is critical for the formation of an effective antitumour adaptive immune response, targeting autophagy pathways in both tumour cells and innate immune cells could enhance tumour clearance. Within tumour cells, autophagy pathways are intertwined with pattern recognition receptor (PRR), inflammatory and cell death pathways, and therefore can alter the immunogenicity of the TME and development of the antitumour immune response. In innate immune cells, autophagy components can have autophagy-independent roles in functional pathways, and therefore could be valuable targets for enhancing immune cell function in the TME and immunotherapy. This review highlights the individual importance of autophagy and the innate immune response to tumorigenesis, and also explains the complex interactions between these pathways in the TME.

Keywords: autophagy; cancer; immunotherapy; innate immune response; tumour microenvironment.

Fig. 1

Role of autophagy at different stages of tumorigenesis. Autophagy has different effects at different stages of tumorigenesis. In tumour initiation (A), autophagy limits the production of DNA‐damaging agents such as ROS in response to cellular stress. Additionally, autophagy has been shown to promote several aspects of senescence in tumour cells, which can result in decreased tumour growth. During tumour growth, autophagy enhances tumour cell survival via increasing resistance to metabolic changes and hypoxia within the tumour microenvironment (B). Autophagy can also enhance tumour cell metastasis via interacting with pathways involved in cell motility and invasion (C). Additionally, autophagy can modify the secretome in the tumour microenvironment to promote invasion into the vasculature and establishment at distal sites.

Fig. 2

Role of the innate immune response at different stages of tumorigenesis. Chronic inflammation can stimulate tumour initiation via the production of DNA‐damaging agents such as ROS (A). Additionally, certain oncogenes can feedback into this process by potentiating pathways in tumour cells. Myeloid cells have been shown to contribute to this process via the generation of DNA‐damaging agents. During tumour growth, tumour cells release DAMPs into the tumour microenvironment (B). Damage‐associated molecular patterns (DAMPs) can be sensed by pattern recognition receptors (PRRs) on stromal cells, causing these cells to release growth factors and inflammatory cytokines, which can promote tumour survival. Inflammatory cytokines activate NFκB in tumour cells, which can stimulate cell survival pathways. The inflammatory microenvironment can stimulate innate immune cells such as tumour‐associated macrophages (TAMs), which can feed back into the inflammatory microenvironment, whereas other innate immune cells play an antitumorigenic role such as natural killer (NK) cells and dendritic cells (DCs). The innate immune response also enhances metastasis via inflammation, which can increase epithelial‐to‐mesenchymal transition and cell migration (C).