MTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment.

Sahar Mafi,Behzad Mansoori,Reza Abbasi,Davoud Rostamzadeh,William C Cho,Shahram Taeb,Hossein Sadeghi

doi:10.3389/fimmu.2021.774103

Abstract

The mechanistic/mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, which plays a pivotal role in regulating numerous cellular functions including cell growth, proliferation, survival, and metabolism by integrating a variety of extracellular and intracellular signals in the tumor microenvironment (TME). Dysregulation of the mTOR pathway is frequently reported in many types of human tumors, and targeting the PI3K/Akt/mTOR signaling pathway has been considered an attractive potential therapeutic target in cancer. The PI3K/Akt/mTOR signaling transduction pathway is important not only in the development and progression of cancers but also for its critical regulatory role in the tumor microenvironment. Immunologically, mTOR is emerging as a key regulator of immune responses. The mTOR signaling pathway plays an essential regulatory role in the differentiation and function of both innate and adaptive immune cells. Considering the central role of mTOR in metabolic and translational reprogramming, it can affect tumor-associated immune cells to undergo phenotypic and functional reprogramming in TME. The mTOR-mediated inflammatory response can also promote the recruitment of immune cells to TME, resulting in exerting the anti-tumor functions or promoting cancer cell growth, progression, and metastasis. Thus, deregulated mTOR signaling in cancer can modulate the TME, thereby affecting the tumor immune microenvironment. Here, we review the current knowledge regarding the crucial role of the PI3K/Akt/mTOR pathway in controlling and shaping the immune responses in TME.

Highlights

The mammalian target of rapamycin is a ubiquitous serine/threonine-specific protein kinase, plays a critical role in regulating numerous cellular functions, including cell growth, proliferation, survival, protein synthesis, ribosome biogenesis, autophagy, and metabolism [1, 2]. mTOR functions within two functionally mTOR in Cancer and tumor microenvironment (TME) and structurally distinct multi-component kinase complexes called mTOR complex 1 and mTOR complex 2 that act as the central nodes of the phosphoinositide 3-kinase (PI3K)/Akt downstream signaling pathway [3]
As the core regulator of metabolic and translational reprogramming, mTOR is mainly involved in the central tumor immune microenvironment, affecting tumor-associated immune cells to undergo phenotypic and functional reprogramming in TME
It is well established that upregulation of the PI3K/Akt/mTOR network is critical in promoting tumor pathogenesis by shaping the characterization and the activity of the TME’s elements specially recruited immune cells

Summary

INTRODUCTION

The mammalian target of rapamycin (mTOR; officially known as the mechanistic target of rapamycin) is a ubiquitous serine/threonine-specific protein kinase, plays a critical role in regulating numerous cellular functions, including cell growth, proliferation, survival, protein synthesis, ribosome biogenesis, autophagy, and metabolism [1, 2]. mTOR functions within two functionally. MTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3 kinase; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; RAPTOR, regulatory-associated protein of mTOR; RICTOR, rapamycin-insensitive companion of mTOR; mSIN1, mammalian stress-activated protein kinase interacting protein; eIF4E, eukaryotic initiation factor 4E; 4EBP1, eIF4E -binding protein 1; S6K1, S6 kinase 1; HIF-1a, Hypoxia Inducible Factor 1a; PKC, Protein kinase C; AMPK, AMP activated protein kinase; SGK1, glucocorticoid regulated kinase 1; FKBP12, FK506 Binding Protein 12; LKB1, liver kinase B1; DEPTOR, DEP-containing mTOR interacting protein; mLST8, mammalian lethal with Sec protein; RAPTOR, regulatory-associated protein of mTOR; PRAS40, proline-rich AKT substrate 40 kDa; mSin, mammalian stress-activated protein kinase (SAPK)-interacting protein 1; Rheb, RAs homologue enriched in brain; TSC, tuberous sclerosis complex; GSK3, Glycogen synthase kinase-3; PDK1, Phosphoinositide-dependent Kinase 1; FOXO3, Forkhead box family transcription factors 3; PTEN, phosphatase and tensin homologue; REDD1, regulated in development and DNA damage responses 1. Further understanding of mTORC2 dysregulation and its physiological functions holds enormous potential to bring regarding that mTORC2 could serve as a novel and amenable therapeutic targets for human disorders, including cancer

THE CRITICAL ROLE OF mTOR SIGNALING PATHWAY IN CANCER

Consequences of the alteration

CONCLUSION

Findings

AUTHOR CONTRIBUTIONS