Autophagy in the Tumor Microenvironment

By Christina Towers, PhD.

The last 20 years of cancer research have taught us the vast complexities of this life-altering disease. In the last 5 years we have realized that those complexities might extend beyond the cancer cells.  The role of the tumor microenvironment (TME) is now front and center in almost every aspect of cancer biology, and autophagy is no exception.  The TME consists of a gamut of different cell types that include supporting stroma like fibroblasts and endothelial cells, as well as immune cells. Recent reports have indicated an important role for autophagy in the crosstalk between tumor cells and the TME. 

Cancer cell-associated autophagy in the TME crosstalk

Cancer cell-associated autophagy can affect cell-cell communication via regulation of the secretome, including cytokines and growth factors, which may affect both neighboring cancer cells as well as other cell types that make up the TME¹.  Recent studies have also heavily implicated autophagy in immuno-evasion which may derail antitumor immunity. Mouse models with a host of tumor types have shown that genetic inhibition of autophagy not only affects tumor cell growth, but also increases host antitumor immunosurveillance, by increasing cytotoxic killing via CD8+ T-Cells^2-4. A dominant negative ATG4B pancreatic ductal adenocarcinoma (PDAC) mouse model, which allows for temporal and spatial control of  autophagy inhibition, showed that in an autochthonous model autophagy inhibition dramatically restricts tumor growth. However, when ATG4BCA+ (autophagy deficient) cells were implanted into nude mice, there was no tumor regression compared to autophagy-intact cells. While the mechanisms for these effects are not fully understood, it’s thought that autophagy may play a role in regulating cell surface expression of DAMPs and other immunoserveillance markers.  Indeed, this most recent PDAC study showed that autophagy inhibition resulted in an increase in infiltrating anti-tumor T-cells and CD68+ macrophages⁵.

Immunocytochemistry/Immunofluorescence: ATG4B Antibody [NBP2-57210] - Staining of human cell line RT4 shows localization to nucleoplasm & cytosol.

TME-associated autophagy in cancer cell crosstalk

Autophagy in the microenvironment can also have profound effects on the tumor cells themselves.  In pancreatic cancer, autophagy in the supporting pancreatic stellate cells is critical for tumor cell growth, as specific inhibition of autophagy in this cell type reduces the amount of alanine that the tumor cells can take up and dramatically restricts their metabolism and growth⁶. Likewise, an elegant drosophilia melanogaster model showed that early stage tumor development is dependent on TME-associated autophagy.  When dormant, autophagy-deficient cancer cells were implanted into autophagy-proficient hosts, the cells resumed tumor growth⁷. 

Significance

It is critical to fully understand the role of the immune system and other supporting cells that make up the TME and how autophagy may affect the cross-talk between these cell types and the tumor cells.  Importantly however, all of these studies fully support pharmacological autophagy inhibition as a viable therapy in patients. Currently, available drugs used for autophagy inhibition in clinical trials target autophagy in both the cancer cells as well as the TME. 

Autophagy Webinar

Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.

References

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