Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity

Abstract

Autophagy is a catabolic intracellular nutrient-scavenging pathway triggered by nutrient deprivation and stress that captures and degrades intracellular proteins and organelles in lysosomes. The breakdown products are then recycled into metabolic pathways to sustain survival. Organelle turnover by autophagy contributes to quality control and suppresses inflammation. Autophagy is upregulated in many cancers and supports their growth, survival, and malignancy in a tumor cell-autonomous fashion. Host autophagy also promotes tumor growth by maintaining a supply of essential nutrients and suppressing innate and adaptive antitumor immune responses. Autophagy is also upregulated in response to cancer therapy and confers treatment resistance. Thus, autophagy is a cancer vulnerability and its inhibition is under investigation as a novel therapeutic approach.

Keywords: T cells; autophagy; cancer; immune response; interferon; metabolism.

Figure 1.. Cancer cells activate autophagy to promote survival.

General scheme for the capture and degradation of autophagy cargo in both normal and cancer cells. Cancer cells upregulate autophagy and use the breakdown products to sustain nucleotide pools and energy homeostasis and thereby their growth and survival.

Figure 2.. Functional interaction of autophagy and stress response pathways.

Autophagy suppresses p53 and thereby apoptosis and neurodegeneration. p53 in turn activates autophagy providing a negative feedback loop. Autophagy and NRF2 functionally complement each other to suppress oxidative stress and loss of both is synthetically lethal in vivo. Autophagy and LKB1 functionally complement each other and loss of both is synthetically lethal in vivo. Pink arrows indicate synthetic lethality.

Figure 3.. Tumor cell autonomous and non-autonomous mechanisms by which autophagy promotes tumor metabolism.

(A), In tumor cells autophagy recycles macromolecules to sustain the supply of substrates to the TCA cycle when nutrients are limiting, which enables continued nucleotide synthesis and energy homeostasis. (B), Host autophagy maintains circulating arginine levels by preventing the release of Arginase 1 from hepatocytes. Arginine is an essential tumor nutrient and its loss from the circulation in autophagy-deficient mice blocks tumor growth.

Figure 4.. Autophagy suppresses innate and adaptive immune responses to promote tumor immune tolerance.

Liver autophagy suppresses STING and IFNγ activation to prevent tumor killing by T cells in MHC-I-dependent fashion. In pancreas cancer autophagy suppresses cell surface expression of MHC-I to promote immune evasion.