Translational Landscape of mTOR Signaling in Integrating Cues Between Cancer and Tumor Microenvironment

  • Chiara Bazzichetto
  • Fabiana Conciatori
  • Italia Falcone
  • Ludovica CiuffredaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1223)


The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental paracrine and autocrine stimuli in tumor microenvironment (TME) constituents. Recently, further efforts have been employed to understand how the mTOR signal transduction mechanisms modulate the sensitivity and resistance to targeted therapies, also for its involvement of mTOR also in modulating angiogenesis and tumor immunity. Indeed, interest in mTOR targeting was increased to improve immune response against cancer and to develop new long-term efficacy strategies, as demonstrated by clinical success of mTOR and immune checkpoint inhibitor combinations. In this chapter, we will describe the role of mTOR in modulating TME elements and the implication in its targeting as a great promise in clinical trials.


mTOR pathway mTORC1 mTORC2 Cancer TME Tumor–stroma interactions Targeted therapy Combination therapy Angiogenesis Immunotherapy 


  1. 1.
    Conciatori F, Ciuffreda L, Bazzichetto C, Falcone I, Pilotto S, Bria E, Cognetti F, Milella M (2018) mTOR Cross-talk in cancer and potential for combination therapy. Cancers (Basel) 10(1). Scholar
  2. 2.
    Watanabe R, Wei L, Huang J (2011) mTOR signaling, function, novel inhibitors, and therapeutic targets. J Nucl Med 52(4):497–500. Scholar
  3. 3.
    Mann WA, Brewer HB Jr, Greten H (1991) Genetic variants of apo E: significance for triglyceride metabolism. Z Gastroenterol Verh 26:106PubMedGoogle Scholar
  4. 4.
    Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137(5):873–886. Scholar
  5. 5.
    Kim SG, Hoffman GR, Poulogiannis G, Buel GR, Jang YJ, Lee KW, Kim BY, Erikson RL, Cantley LC, Choo AY, Blenis J (2013) Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol Cell 49(1):172–185. Scholar
  6. 6.
    Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496–1501. Scholar
  7. 7.
    Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302. Scholar
  8. 8.
    Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20(20):2820–2832. Scholar
  9. 9.
    Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127(1):125–137. Scholar
  10. 10.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. Scholar
  11. 11.
    Cybulski N, Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 34(12):620–627. Scholar
  12. 12.
    Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10(14):2305–2316. Scholar
  13. 13.
    Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Ruegg MA, Hall MN (2012) Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 15(5):725–738. Scholar
  14. 14.
    Saxton RA, Sabatini DM (2017) mTOR Signaling in growth, metabolism, and disease. Cell 169(2):361–371. Scholar
  15. 15.
    Conciatori F, Bazzichetto C, Falcone I, Pilotto S, Bria E, Cognetti F, Milella M, Ciuffreda L (2018) Role of mTOR Signaling in tumor microenvironment: an overview. Int J Mol Sci 19(8). Scholar
  16. 16.
    Araki K, Ellebedy AH, Ahmed R (2011) TOR in the immune system. Curr Opin Cell Biol 23(6):707–715. Scholar
  17. 17.
    Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC (2016) Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res 18(1):84. Scholar
  18. 18.
    Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66(11):5549–5554. Scholar
  19. 19.
    Maxwell PJ, Coulter J, Walker SM, McKechnie M, Neisen J, McCabe N, Kennedy RD, Salto-Tellez M, Albanese C, Waugh DJ (2013) Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN-deficient prostate carcinoma. Eur Urol 64(2):177–188. Scholar
  20. 20.
    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401. Scholar
  21. 21.
    Duluc C, Moatassim-Billah S, Chalabi-Dchar M, Perraud A, Samain R, Breibach F, Gayral M, Cordelier P, Delisle MB, Bousquet-Dubouch MP, Tomasini R, Schmid H, Mathonnet M, Pyronnet S, Martineau Y, Bousquet C (2015) Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance. EMBO Mol Med 7(6):735–753. Scholar
  22. 22.
    Pepper M, Jenkins MK (2011) Origins of CD4(+) effector and central memory T cells. Nat Immunol 12(6):467–471CrossRefGoogle Scholar
  23. 23.
    Powell JD, Delgoffe GM (2010) The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33(3):301–311. Scholar
  24. 24.
    Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30(6):832–844. Scholar
  25. 25.
    Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12(4):295–303. Scholar
  26. 26.
    Valmori D, Tosello V, Souleimanian NE, Godefroy E, Scotto L, Wang Y, Ayyoub M (2006) Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells. J Immunol 177(2):944–949. Scholar
  27. 27.
    Haxhinasto S, Mathis D, Benoist C (2008) The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 205(3):565–574. Scholar
  28. 28.
    Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16(2):178–187. Scholar
  29. 29.
    Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490. Scholar
  30. 30.
    Pollizzi KN, Powell JD (2015) Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol 36(1):13–20. Scholar
  31. 31.
    Salmond RJ (2018) mTOR regulation of glycolytic metabolism in T cells. Front Cell Dev Biol 6:122. Scholar
  32. 32.
    Rao RR, Li Q, Odunsi K, Shrikant PA (2010) The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32(1):67–78. Scholar
  33. 33.
    Wu T, Wieland A, Araki K, Davis CW, Ye L, Hale JS, Ahmed R (2012) Temporal expression of microRNA cluster miR-17-92 regulates effector and memory CD8+ T-cell differentiation. Proc Natl Acad Sci U S A 109(25):9965–9970. Scholar
  34. 34.
    Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT, Wen J, Delgoffe GM, Powell JD (2015) mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J Clin Invest 125(5):2090–2108. Scholar
  35. 35.
    Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150. Scholar
  36. 36.
    Welte T, Kim IS, Tian L, Gao X, Wang H, Li J, Holdman XB, Herschkowitz JI, Pond A, Xie G, Kurley S, Nguyen T, Liao L, Dobrolecki LE, Pang L, Mo Q, Edwards DP, Huang S, Xin L, Xu J, Li Y, Lewis MT, Wang T, Westbrook TF, Rosen JM, Zhang XH (2016) Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat Cell Biol 18(6):632–644. Scholar
  37. 37.
    Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21(3):309–322. Scholar
  38. 38.
    Mercalli A, Calavita I, Dugnani E, Citro A, Cantarelli E, Nano R, Melzi R, Maffi P, Secchi A, Sordi V, Piemonti L (2013) Rapamycin unbalances the polarization of human macrophages to M1. Immunology 140(2):179–190. Scholar
  39. 39.
    Jiang H, Westerterp M, Wang C, Zhu Y, Ai D (2014) Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice. Diabetologia 57(11):2393–2404. Scholar
  40. 40.
    Hallowell RW, Collins SL, Craig JM, Zhang Y, Oh M, Illei PB, Chan-Li Y, Vigeland CL, Mitzner W, Scott AL, Powell JD, Horton MR (2017) mTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis. Nat Commun 8:14208. Scholar
  41. 41.
    Rajabi M, Mousa SA (2017) The role of angiogenesis in cancer treatment. Biomedicine 5(2). Scholar
  42. 42.
    Krock BL, Skuli N, Simon MC (2011) Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2(12):1117–1133. Scholar
  43. 43.
    Chen W, Ma T, Shen XN, Xia XF, Xu GD, Bai XL, Liang TB (2012) Macrophage-induced tumor angiogenesis is regulated by the TSC2-mTOR pathway. Cancer Res 72(6):1363–1372. Scholar
  44. 44.
    Vinals F, Chambard JC, Pouyssegur J (1999) p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J Biol Chem 274(38):26776–26782. Scholar
  45. 45.
    Sun S, Chen S, Liu F, Wu H, McHugh J, Bergin IL, Gupta A, Adams D, Guan JL (2015) Constitutive activation of mTORC1 in endothelial cells leads to the development and progression of lymphangiosarcoma through VEGF autocrine signaling. Cancer Cell 28(6):758–772. Scholar
  46. 46.
    Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, Elfiky AA, Taplin ME, Stack EC, Signoretti S, Loda M, Shapiro GI, Sabatini DM, Lander ES, Gabriel SB, Kantoff PW, Garraway LA, Rosenberg JE (2014) Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov 4(5):546–553. Scholar
  47. 47.
    Faes S, Santoro T, Demartines N, Dormond O (2017) Evolving significance and future relevance of anti-angiogenic activity of mTOR inhibitors in cancer therapy. Cancers (Basel) 9(11). Scholar
  48. 48.
    Milella M, Falcone I, Conciatori F, Matteoni S, Sacconi A, De Luca T, Bazzichetto C, Corbo V, Simbolo M, Sperduti I, Benfante A, Del Curatolo A, Cesta Incani U, Malusa F, Eramo A, Sette G, Scarpa A, Konopleva M, Andreeff M, McCubrey JA, Blandino G, Todaro M, Stassi G, De Maria R, Cognetti F, Del Bufalo D, Ciuffreda L (2017) PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Sci Rep 7:43013. Scholar
  49. 49.
    Ciuffreda L, Del Curatolo A, Falcone I, Conciatori F, Bazzichetto C, Cognetti F, Corbo V, Scarpa A, Milella M (2017) Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer. Ann Oncol 28(11):2896–2898. Scholar
  50. 50.
    Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39(2):171–183. Scholar
  51. 51.
    Kim LC, Cook RS, Chen J (2017) mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene 36(16):2191–2201. Scholar
  52. 52.
    Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, Ye Q (2017) Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology 66(6):1920–1933. Scholar
  53. 53.
    Kitano H, Kitadai Y, Teishima J, Yuge R, Shinmei S, Goto K, Inoue S, Hayashi T, Sentani K, Yasui W, Matsubara A (2017) Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma. Cancer Med 6(10):2308–2320. Scholar
  54. 54.
    Bruning U, Morales-Rodriguez F, Kalucka J, Goveia J, Taverna F, Queiroz KCS, Dubois C, Cantelmo AR, Chen R, Loroch S, Timmerman E, Caixeta V, Bloch K, Conradi LC, Treps L, Staes A, Gevaert K, Tee A, Dewerchin M, Semenkovich CF, Impens F, Schilling B, Verdin E, Swinnen JV, Meier JL, Kulkarni RA, Sickmann A, Ghesquiere B, Schoonjans L, Li X, Mazzone M, Carmeliet P (2018) Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. Cell Metab 28(6):866–880, e815. Scholar
  55. 55.
    Deng F, Zhou R, Lin C, Yang S, Wang H, Li W, Zheng K, Lin W, Li X, Yao X, Pan M, Zhao L (2019) Tumor-secreted dickkopf2 accelerates aerobic glycolysis and promotes angiogenesis in colorectal cancer. Theranostics 9(4):1001–1014. Scholar
  56. 56.
    Smyth MJ, Ngiow SF, Ribas A, Teng MW (2016) Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 13(3):143–158. Scholar
  57. 57.
    Tormoen GW, Crittenden MR, Gough MJ (2018) Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol 3(4):520–526. Scholar
  58. 58.
    Umansky V, Sevko A (2013) Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron 6(2):169–177. Scholar
  59. 59.
    Abu-Eid R, Samara RN, Ozbun L, Abdalla MY, Berzofsky JA, Friedman KM, Mkrtichyan M, Khleif SN (2014) Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol Res 2(11):1080–1089. Scholar
  60. 60.
    Gato-Canas M, Martinez de Morentin X, Blanco-Luquin I, Fernandez-Irigoyen J, Zudaire I, Liechtenstein T, Arasanz H, Lozano T, Casares N, Chaikuad A, Knapp S, Guerrero-Setas D, Escors D, Kochan G, Santamaria E (2015) A core of kinase-regulated interactomes defines the neoplastic MDSC lineage. Oncotarget 6(29):27160–27175. Scholar
  61. 61.
    O’Donnell JS, Massi D, Teng MWL, Mandala M (2018) PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol 48:91–103. Scholar
  62. 62.
    Shen X, Zhao B (2018) Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ 362:k3529. Scholar
  63. 63.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. Scholar
  64. 64.
    Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, Kitagawa H, Kawabata S, Taube JM, Yao S, Liu LN, Gills JJ, Dennis PA (2016) Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res 76(2):227–238. Scholar
  65. 65.
    Song M, Chen D, Lu B, Wang C, Zhang J, Huang L, Wang X, Timmons CL, Hu J, Liu B, Wu X, Wang L, Wang J, Liu H (2013) PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PLoS One 8(6):e65821. Scholar
  66. 66.
    Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, Chawla A, Curran M, Hwu P, Sharma P, Litton JK, Molldrem JJ, Alatrash G (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370. Scholar
  67. 67.
    Saunders RN, Metcalfe MS, Nicholson ML (2001) Rapamycin in transplantation: a review of the evidence. Kidney Int 59(1):3–16. Scholar
  68. 68.
    Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB (2014) mTOR inhibition improves immune function in the elderly. Sci Transl Med 6(268):268ra179. Scholar
  69. 69.
    Pedicord VA, Cross JR, Montalvo-Ortiz W, Miller ML, Allison JP (2015) Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming to promote memory formation and metabolic readiness. J Immunol 194(5):2089–2098. Scholar
  70. 70.
    Langdon S, Hughes A, Taylor MA, Kuczynski EA, Mele DA, Delpuech O, Jarvis L, Staniszewska A, Cosulich S, Carnevalli LS, Sinclair C (2018) Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity. Oncoimmunology 7(8):e1458810. Scholar
  71. 71.
    Jiang Q, Weiss JM, Back T, Chan T, Ortaldo JR, Guichard S, Wiltrout RH (2011) mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res 71(12):4074–4084. Scholar
  72. 72.
    Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88. Scholar
  73. 73.
    Zhao L, Li C, Liu F, Zhao Y, Liu J, Hua Y, Liu J, Huang J, Ge C (2017) A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/Akt/mTOR signaling pathway. Onco Targets Ther 10:2115–2126. Scholar
  74. 74.
    Weekes CD, Song D, Arcaroli J, Wilson LA, Rubio-Viqueira B, Cusatis G, Garrett-Mayer E, Messersmith WA, Winn RA, Hidalgo M (2012) Stromal cell-derived factor 1alpha mediates resistance to mTOR-directed therapy in pancreatic cancer. Neoplasia 14(8):690–701. Scholar
  75. 75.
    Ierano C, Santagata S, Napolitano M, Guardia F, Grimaldi A, Antignani E, Botti G, Consales C, Riccio A, Nanayakkara M, Barone MV, Caraglia M, Scala S (2014) CXCR4 and CXCR7 transduce through mTOR in human renal cancer cells. Cell Death Dis 5:e1310. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Chiara Bazzichetto
    • 1
  • Fabiana Conciatori
    • 1
  • Italia Falcone
    • 1
  • Ludovica Ciuffreda
    • 2
    Email author
  1. 1.Medical Oncology 1IRCCS—Regina Elena National Cancer InstituteRomeItaly
  2. 2.SAFU, Department of Research, Advanced Diagnostics, and Technological InnovationIRCCS—Regina Elena National Cancer InstituteRomeItaly

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