Abstract
The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy.
Highlights
The mammalian target of rapamycin forms two functionally and structurally distinct multi-component complexes, named mTOR complex 1 and mTOR complex 2
We describe the role of mTOR in tumor and non-tumor cells in order to better analyze the mechanisms of cancer progression and metastasis as well as drug resistance development
MTOR forms two functional multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the different binding partners that confer distinguishing functions upon them. mTORC1 includes mTOR, raptor, proline-rich AKT substrate 40 (PRAS40), DEP domain-containing mTOR interacting protein (DEPTOR), mammalian lethal with sec13 protein 8, Rac1, GRp58, Tel2-interacting protein 1 (Tti1) and Telomere maintenance 2 (Tel2), while mTORC2 includes rictor, mammalian stress-activated protein kinase interacting protein 1, protein observed with rictor (Protor) 1/2, proline-rich protein 5 (PRR5), and heat shock protein 70 (Hsp70), in addition to mTOR, DEPTOR, mLST8, Rac1, GRp58, and Tti1 and Tel2 [1]
Summary
The mammalian target of rapamycin (mTOR) forms two functionally and structurally distinct multi-component complexes, named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) These two complexes regulate several physiological processes, such as protein synthesis, biosynthesis of macromolecules, cytoskeleton remodeling, angiogenesis, homeostasis, survival, metabolism, autophagy, and response to stress [1]. MTORC1 includes mTOR, raptor, proline-rich AKT substrate 40 (PRAS40), DEP domain-containing mTOR interacting protein (DEPTOR), mammalian lethal with sec protein 8 (mLST8), Rac, GRp58, Tel2-interacting protein 1 (Tti1) and Telomere maintenance 2 (Tel2), while mTORC2 includes rictor, mammalian stress-activated protein kinase interacting protein 1 (mSIN1), protein observed with rictor (Protor) 1/2, proline-rich protein 5 (PRR5), and heat shock protein 70 (Hsp70), in addition to mTOR, DEPTOR, mLST8, Rac, GRp58, and Tti and Tel2 [1] In both complexes, the mTOR kinase acts as the central catalytic component, whereas the scaffolding protein mLST8, the regulatory subunit DEPTOR, and Tti1/Tel act as important regulators of assembly and stability. Recent evidence shows that treatment with PI3K-AKT-mTOR signaling inhibitors affects the tumor progression, and tumor immunosurveillance within the TME [17]
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