mTOR Signaling and the Tumor Microenvironment

By Yoskaly Lazo-Fernandez, PhD

The mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that, as a member of two distinct intracellular protein complexes, mTORC1 and mTORC2, regulates protein synthesis, autophagy metabolism, proliferation and survival. More and more research is showing how the catalytic activity of both mTOR complexes plays an important role in cancer biology. Not only mTOR is upregulated and contributes to the development of numerous cancer types, but it also contributes to the angiogenic and immune responses within the tumor microenvironment (TME)¹.

Immunohistochemistry-Paraffin: TOR/mTOR Antibody (274) [NBP2-61590] - Staining of formalin fixed and paraffin embedded human breast cancer tissue sections using Anti-mTOR Rabbit Monoclonal Antibody at a 1:1000 dilution.

mTOR in cancer cells

Although in itself mTOR is not an oncogene, as part of the PI3K/Akt signaling network, mTOR is a powerful stimulator of cell proliferation. As such, it is frequently activated in cancer cells where it can strongly support tumor growth. Specifically, mTORC1 supports rapid proliferation by activating transcription regulators such as HIF-1 alpha and S6K1, which respectively drive and regulate the expression of genes involved in aerobic glycolysis, as well as in lipogenesis and protein synthesis. Upregulation of mTORC2 also plays a role in cancer biology, as it activates PKB (also named AKT), PKC, SGK3 and FoxO1/3 transcription factors, overall promoting proliferation and survival under oxygen and/nutrient deprivation².

mTOR in immune cells

The activity of both mTORC1 and mTORC2 induces CD4+ helper T cells to differentiate and expand into Th1 and Th2 subtypes³. As such, pharmacological antagonism of mTOR reduces CD4+ helper T cell abundance while expanding inhibitory FOXP3+ regulatory cells, a response that is used clinically to produce immunosuppression in organ transplant patients.

The activity of CD8+ effector T-cells is also regulated by mTOR. Activated mTORC1 causes a strong stimulation of cytotoxic T-cell function while activation of mTORC2 in CD8+ cells seems to reduce the formation of memory T-cells⁴.

New research is emerging linking mTOR activity in other cell types with an antitumor immune response. For example, mTOR complexes have been found to induce maturation, survival, proliferation and function of both B cell and Natural killer (NK) cells. In addition, mTOR complexes regulate macrophage polarization, although the specific role of mTOR in this context is not well understood yet^5,6.

Immunohistochemistry-Paraffin: VEGF Antibody (VG1) [NB100-664] - FFPE human angiosarcoma tissue section using VEGF antibody (clone VG1). The endothelial cells of the blood vessels and most of the cancer cells showed strong positivity for VEGF protein.

mTOR and angiogenesis

The activation of mTOR complexes in both, cancer cells and in endothelial cells plays an essential role in tumor angiogenesis. Tumor hypoxia upregulates the transcription factor hypoxia-inducible factor 1 (HIF-1) which leads to the transcription and secretion of angiogenic factors such as VEGF. Activation of mTORC1 contributes to this angiogenic response by stimulating HIF-1 alpha mRNA translation which in turn stabilizes HIF-1 (as HIF-1 is a heterodimer composed of HIF-1 alpha and the constitutively expressed HIF-1 beta). Interestingly, upon VEGF binding in the vasculature, stimulation of endothelial cell proliferation occurs through activation of both mTORC1 and mTORC2. In addition, mTOR has been shown to stimulate the angiogenic effects of macrophages within the TME⁷.

Significance

The important role of mTOR in the biology of cancer development, TME establishment and tumor immunology highlights the potential of this kinase for anticancer pharmacological modulation, along with the importance of other upstream or downstream potential targets. In fact, some mTOR inhibitors have already been approved for the treatment of a few specific cancers, including advanced renal cell carcinoma. A very active research effort is underway to study the preclinical and clinical effects of mTOR inhibitors, alone and in combination with other drugs, such as Akt inhibitors. Exciting new results are warranted.

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Yoskaly Lazo Fernandez, PhD
Research Assistant Professor, The University of Kansas Medical Center
Dr. Lazo-Fernandez is interested in the application of novel immunotherapies for the treatment of cancer, particularly ovarian cancer.

References

1. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annual review of immunology. 2012;30:39-68. doi:10.1146/annurev-immunol-020711-075024.
2. Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends in Pharmacological Sciences. 2015;36(2):124-135. doi:10.1016/j.tips.2014.11.004.
3. Lee K, Gudapati P, jan Dragovic, Spencer C, Joyce S, Killeen N, Magnuson MA, Boothby M. Mammalian Target of Rapamycin Protein Complex 2 Regulates Differentiation of Th1 and Th2 Cell Subsets via Distinct Signaling Pathways. Immunity. 2010;32(6):743-753. doi:10.1016/j.immuni.2010.06.002.
4. Pollizzi KN, Patel CH, Sun I-H, Oh M-H, Waickman AT, Wen J, Delgoffe GM, Powell JD. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. Journal of Clinical Investigation. 2015;125(5):2090-2108. doi:10.1172/JCI77746 .
5. Zeng H. mTOR signaling in immune cells and its implications for cancer immunotherapy. Cancer Letters. 2017;408:182-189. doi:10.1016/j.canlet.2017.08.038.
6. Weichhart T, Hengstschläger M, Linke M. Regulation of innate immune cell function by mTOR. Nature Reviews Immunology. 2015;15(10):599-614. doi:10.1038/nri3901.
7. Faes S, Santoro T, Demartines N, Dormond O. Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy. Cancers. 2017;9(11):152. doi:10.3390/cancers9110152 .