Recent Advances of Autophagy in Non-Small Cell Lung Cancer: From Basic Mechanisms to Clinical Application

Abstract

Lung cancer is characterized by the most common oncological disease and leading cause of cancer death worldwide, of which a group of subtypes known as non-small cell lung cancer (NSCLC) accounts for approximately 85%. In the past few decades, important progression in the therapies of NSCLC has enhanced our understanding of the biology and progression mechanisms of tumor. The application of immunotherapy and small molecule tyrosine kinase inhibitors has brought significant clinical benefits in certain patients. However, early metastasis and the emergence of resistance to antitumor therapy have resulted in the relatively low overall cure and survival rates for NSCLC. Autophagy is a conserved process that allows cells to recycle unused or damaged organelles and cellular components. It has been reported to be related to the progression of NSCLC and resistance to targeted therapy and cytotoxic chemotherapy. Therefore, autophagy is considered as a potential therapeutic target for NSCLC. Mounting results have been reported about the combination of tyrosine kinase inhibitors and inhibitors of autophagy in models of NSCLC. This review aims to provide a comprehensive review on the roles of autophagy in NSCLC, focusing on related clinical data of agents that regulate autophagy in NSCLC. Furthermore, this study will provide a theoretical basis for further improvement of autophagy-based cancer therapy.

Keywords: autophagy; immunotherapy; non-small cell lung cancer; resistance; tyrosine kinase inhibitors.

Figure 1

The autophagy pathway and multiple stages can be inhibited. The autophagy pathway consists 5 steps. Intracellular membranes are prepared by initiation and vesicle nucleation to form AVs through the formation of PI3P on membranes. Next, LC3-I is conjugated to PE on emerging AVs. Subsequently, LC3 is docked with the cargo adapter so that the cargo can be loaded into the AVs. After AVs matures, it fuses with lysosomes to complete the degradation of cargo and the recycling of nutrients. Autophagy inhibitors are shown in green boxes.

Figure 2

A schematic representation of the role of autophagy in cancer cells and non-cancer cells.

Figure 3

Autophagy-mediated immune evasion of cancer cells: Knockdown of ATG7, or dominant negative expression of ATG4B or treatment of chloroquine leads to the inhibition of autophagy, which induces the accumulation of MHC-I on the surface of cancer cell. The MHC-I accumulation promotes the recognition and effect of CD8⁺ T cells on cancer cells. Likewise, inhibiting autophagy results in the infiltration of TAMs and the conversion of macrophages from M2 to M1 phenotype, thereby enhancing the antitumor activity. What is noteworthy is that impairment of LAP results in activation of T cells mediated by STING, producing granzyme B and IFN-γ to kill the cancer cells. In addition, the combination of PIK3C3/VPS34 inhibitors with anti-PD-1 and PD-L1 therapy could increase the numbers of NK and CD8⁺, CD4⁺ T cells, macrophages and dendritic cells along with CCL5 and CXCL10 infiltrating in tumor environment. Moreover, SKIL promoted tumorigenesis and immune escape of NSCLC cells by up-regulating the TAZ/autophagy axis and inhibition on downstream STING pathway, thereby resulting in reducing T cell infiltration and release of chemokines including CXCL10, CCL5 and IFN-β.