Skip to main content
Erschienen in: Cancer Immunology, Immunotherapy 8/2021

Open Access 03.02.2021 | Review

Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment

verfasst von: Varun Sasidharan Nair, Reem Saleh, Salman M. Toor, Farhan S. Cyprian, Eyad Elkord

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 8/2021

Einloggen, um Zugang zu erhalten

Abstract

Metabolic dysregulation in the hypoxic tumor microenvironment (TME) is considered as a hallmark of solid tumors, leading to changes in biosynthetic pathways favoring onset, survival and proliferation of malignant cells. Within the TME, hypoxic milieu favors metabolic reprogramming of tumor cells, which subsequently affects biological properties of tumor-infiltrating immune cells. T regulatory cells (Tregs), including both circulating and tissue-resident cells, are particularly susceptible to hypoxic metabolic signaling that can reprogram their biological and physicochemical properties. Furthermore, metabolic reprogramming modifies Tregs to utilize alternative substrates and undergo a plethora of metabolic events to meet their energy demands. Major impact of this metabolic reprogramming can result in differentiation, survival, excessive secretion of immunosuppressive cytokines and proliferation of Tregs within the TME, which in turn dampen anti-tumor immune responses. Studies on fine-tuning of Treg metabolism are challenging due to heterogenicity of tissue-resident Tregs and their dynamic functions. In this review, we highlight tumor intrinsic and extrinsic factors, which can influence Treg metabolism in the hypoxic TME. Moreover, we focus on metabolic reprogramming of Tregs that could unveil potential regulatory networks favoring tumorigenesis/progression, and provide novel insights, including inhibitors against acetyl-coA carboxylase 1 and transforming growth factor beta into targeting Treg metabolism for therapeutic benefits.
Literatur
9.
Zurück zum Zitat Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949. https://doi.org/10.1038/nm1093CrossRefPubMed Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949. https://​doi.​org/​10.​1038/​nm1093CrossRefPubMed
13.
21.
Zurück zum Zitat Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR, Sendor AB, Chiang YJ, Corona AL, Gemta LF, Vincent BG, Wang RC, Kim B, Hong J, Chen CL, Bullock TN, Irish JM, Rathmell WK, Rathmell JC (2017) Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. https://doi.org/10.1172/jci.insight.93411 Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR, Sendor AB, Chiang YJ, Corona AL, Gemta LF, Vincent BG, Wang RC, Kim B, Hong J, Chen CL, Bullock TN, Irish JM, Rathmell WK, Rathmell JC (2017) Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. https://​doi.​org/​10.​1172/​jci.​insight.​93411
28.
Zurück zum Zitat Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109(9):3812–3819. https://doi.org/10.1182/blood-2006-07-035972CrossRefPubMed Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109(9):3812–3819. https://​doi.​org/​10.​1182/​blood-2006-07-035972CrossRefPubMed
35.
Zurück zum Zitat Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davis W, Xu X, Karakousis GC, Schuchter LM, Xu W, Amaravadi R, Xiao M, Sadek N, Krepler C, Herlyn M, Freeman GJ, Rabinowitz JD, Ertl HCJ (2017) Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32(3):377–391 e379. https://doi.org/10.1016/j.ccell.2017.08.004 Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davis W, Xu X, Karakousis GC, Schuchter LM, Xu W, Amaravadi R, Xiao M, Sadek N, Krepler C, Herlyn M, Freeman GJ, Rabinowitz JD, Ertl HCJ (2017) Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32(3):377–391 e379. https://​doi.​org/​10.​1016/​j.​ccell.​2017.​08.​004
36.
Zurück zum Zitat Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, Zhang P, Panek WK, Cordero A, Han Y, Ahmed AU, Chandel NS, Lesniak MS (2019) HIF-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep 27(1):226–237 e224. https://doi.org/10.1016/j.celrep.2019.03.029 Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, Zhang P, Panek WK, Cordero A, Han Y, Ahmed AU, Chandel NS, Lesniak MS (2019) HIF-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep 27(1):226–237 e224. https://​doi.​org/​10.​1016/​j.​celrep.​2019.​03.​029
37.
40.
Zurück zum Zitat Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761. https://doi.org/10.4049/jimmunol.176.11.6752CrossRefPubMed Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761. https://​doi.​org/​10.​4049/​jimmunol.​176.​11.​6752CrossRefPubMed
44.
Zurück zum Zitat Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911. https://doi.org/10.1016/j.immuni.2009.03.019CrossRefPubMed Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911. https://​doi.​org/​10.​1016/​j.​immuni.​2009.​03.​019CrossRefPubMed
45.
Zurück zum Zitat Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, Nagase H, Nishimura J, Yamamoto H, Takiguchi S, Tanoue T, Suda W, Morita H, Hattori M, Honda K, Mori M, Doki Y, Sakaguchi S (2016) Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 22(6):679–684. https://doi.org/10.1038/nm.4086CrossRefPubMed Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, Nagase H, Nishimura J, Yamamoto H, Takiguchi S, Tanoue T, Suda W, Morita H, Hattori M, Honda K, Mori M, Doki Y, Sakaguchi S (2016) Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 22(6):679–684. https://​doi.​org/​10.​1038/​nm.​4086CrossRefPubMed
50.
Zurück zum Zitat Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, Pasca di Magliano M (2020) Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov 10(3):422–439. https://doi.org/10.1158/2159-8290.CD-19-0958CrossRefPubMedPubMedCentral Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, Pasca di Magliano M (2020) Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov 10(3):422–439. https://​doi.​org/​10.​1158/​2159-8290.​CD-19-0958CrossRefPubMedPubMedCentral
67.
Zurück zum Zitat Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163(10):5211–5218PubMed Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163(10):5211–5218PubMed
69.
Zurück zum Zitat Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ, 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293 e1287. https://doi.org/10.1016/j.cmet.2016.12.018 Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ, 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293 e1287. https://​doi.​org/​10.​1016/​j.​cmet.​2016.​12.​018
70.
Zurück zum Zitat Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM (2017) Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47(5):875–889 e810. https://doi.org/10.1016/j.immuni.2017.10.017 Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM (2017) Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47(5):875–889 e810. https://​doi.​org/​10.​1016/​j.​immuni.​2017.​10.​017
72.
Zurück zum Zitat Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Gobel G, Margreiter R, Konigsrainer A, Fuchs D, Amberger A (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12(4):1144–1151. https://doi.org/10.1158/1078-0432.CCR-05-1966CrossRefPubMed Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Gobel G, Margreiter R, Konigsrainer A, Fuchs D, Amberger A (2006) Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 12(4):1144–1151. https://​doi.​org/​10.​1158/​1078-0432.​CCR-05-1966CrossRefPubMed
73.
Zurück zum Zitat Ino K, Yamamoto E, Shibata K, Kajiyama H, Yoshida N, Terauchi M, Nawa A, Nagasaka T, Takikawa O, Kikkawa F (2008) Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 14(8):2310–2317. https://doi.org/10.1158/1078-0432.CCR-07-4144CrossRefPubMed Ino K, Yamamoto E, Shibata K, Kajiyama H, Yoshida N, Terauchi M, Nawa A, Nagasaka T, Takikawa O, Kikkawa F (2008) Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 14(8):2310–2317. https://​doi.​org/​10.​1158/​1078-0432.​CCR-07-4144CrossRefPubMed
76.
Zurück zum Zitat Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E, Faicchia D, Severa M, Rizzo F, Coccia EM, Bonacina F, Mitro N, Norata GD, Rossetti G, Ranzani V, Pagani M, Giorda E, Wei Y, Matarese G, Barnaba V, Piconese S (2018) Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci U S A 115(28):E6546-e6555. https://doi.org/10.1073/pnas.1720113115CrossRefPubMedPubMedCentral Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E, Faicchia D, Severa M, Rizzo F, Coccia EM, Bonacina F, Mitro N, Norata GD, Rossetti G, Ranzani V, Pagani M, Giorda E, Wei Y, Matarese G, Barnaba V, Piconese S (2018) Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci U S A 115(28):E6546-e6555. https://​doi.​org/​10.​1073/​pnas.​1720113115CrossRefPubMedPubMedCentral
79.
Zurück zum Zitat Lowe MM, Boothby I, Clancy S, Ahn RS, Liao W, Nguyen DN, Schumann K, Marson A, Mahuron KM, Kingsbury GA, Liu Z, Munoz Sandoval P, Rodriguez RS, Pauli ML, Taravati K, Arron ST, Neuhaus IM, Harris HW, Kim EA, Shin US, Krummel MF, Daud A, Scharschmidt TC, Rosenblum MD (2019) Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. https://doi.org/10.1172/jci.insight.129756 Lowe MM, Boothby I, Clancy S, Ahn RS, Liao W, Nguyen DN, Schumann K, Marson A, Mahuron KM, Kingsbury GA, Liu Z, Munoz Sandoval P, Rodriguez RS, Pauli ML, Taravati K, Arron ST, Neuhaus IM, Harris HW, Kim EA, Shin US, Krummel MF, Daud A, Scharschmidt TC, Rosenblum MD (2019) Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. https://​doi.​org/​10.​1172/​jci.​insight.​129756
81.
Zurück zum Zitat Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, Hippen KL, Loschi M, Thangavelu G, Corrado M, Edwards-Hicks J, Grzes KM, Pearce EJ, Blazar BR, Pearce EL (2020) Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for treg suppressive function. Cell Metab 31(2):422–437 e425. https://doi.org/10.1016/j.cmet.2019.11.021 Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, Hippen KL, Loschi M, Thangavelu G, Corrado M, Edwards-Hicks J, Grzes KM, Pearce EJ, Blazar BR, Pearce EL (2020) Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for treg suppressive function. Cell Metab 31(2):422–437 e425. https://​doi.​org/​10.​1016/​j.​cmet.​2019.​11.​021
91.
Zurück zum Zitat Rizzo A, Di Giovangiulio M, Stolfi C, Franze E, Fehling HJ, Carsetti R, Giorda E, Colantoni A, Ortenzi A, Rugge M, Mescoli C, Monteleone G, Fantini MC (2018) RORgammat-expressing tregs drive the growth of colitis-associated colorectal cancer by controlling IL6 in dendritic cells. Cancer Immunol Res 6(9):1082–1092. https://doi.org/10.1158/2326-6066.CIR-17-0698CrossRefPubMed Rizzo A, Di Giovangiulio M, Stolfi C, Franze E, Fehling HJ, Carsetti R, Giorda E, Colantoni A, Ortenzi A, Rugge M, Mescoli C, Monteleone G, Fantini MC (2018) RORgammat-expressing tregs drive the growth of colitis-associated colorectal cancer by controlling IL6 in dendritic cells. Cancer Immunol Res 6(9):1082–1092. https://​doi.​org/​10.​1158/​2326-6066.​CIR-17-0698CrossRefPubMed
93.
105.
Zurück zum Zitat Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109(41):E2784-2793. https://doi.org/10.1073/pnas.1202366109CrossRefPubMedPubMedCentral Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109(41):E2784-2793. https://​doi.​org/​10.​1073/​pnas.​1202366109CrossRefPubMedPubMedCentral
111.
116.
Zurück zum Zitat Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20(11):1327–1333. https://doi.org/10.1038/nm.3704CrossRefPubMed Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20(11):1327–1333. https://​doi.​org/​10.​1038/​nm.​3704CrossRefPubMed
117.
Zurück zum Zitat Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, Lombardo PS, Van Nostrand JL, Hutchins A, Vera L, Gerken L, Greenwood J, Bhat S, Harriman G, Westlin WF, Harwood HJ Jr, Saghatelian A, Kapeller R, Metallo CM, Shaw RJ (2016) Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 22(10):1108–1119. https://doi.org/10.1038/nm.4181CrossRefPubMedPubMedCentral Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, Lombardo PS, Van Nostrand JL, Hutchins A, Vera L, Gerken L, Greenwood J, Bhat S, Harriman G, Westlin WF, Harwood HJ Jr, Saghatelian A, Kapeller R, Metallo CM, Shaw RJ (2016) Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 22(10):1108–1119. https://​doi.​org/​10.​1038/​nm.​4181CrossRefPubMedPubMedCentral
131.
Zurück zum Zitat Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183(9):5458–5467. https://doi.org/10.4049/jimmunol.0803217CrossRefPubMed Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183(9):5458–5467. https://​doi.​org/​10.​4049/​jimmunol.​0803217CrossRefPubMed
137.
Zurück zum Zitat Moretti S, Menicali E, Voce P, Morelli S, Cantarelli S, Sponziello M, Colella R, Fallarino F, Orabona C, Alunno A, de Biase D, Bini V, Mameli MG, Filetti S, Gerli R, Macchiarulo A, Melillo RM, Tallini G, Santoro M, Puccetti P, Avenia N, Puxeddu E (2014) Indoleamine 2,3-dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment. J Clin Endocrinol Metabol 99(5):E832-840. https://doi.org/10.1210/jc.2013-3351CrossRef Moretti S, Menicali E, Voce P, Morelli S, Cantarelli S, Sponziello M, Colella R, Fallarino F, Orabona C, Alunno A, de Biase D, Bini V, Mameli MG, Filetti S, Gerli R, Macchiarulo A, Melillo RM, Tallini G, Santoro M, Puccetti P, Avenia N, Puxeddu E (2014) Indoleamine 2,3-dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment. J Clin Endocrinol Metabol 99(5):E832-840. https://​doi.​org/​10.​1210/​jc.​2013-3351CrossRef
141.
Zurück zum Zitat Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203. https://doi.org/10.1038/nature10491CrossRefPubMed Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203. https://​doi.​org/​10.​1038/​nature10491CrossRefPubMed
145.
Zurück zum Zitat Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F (2011) ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal 4(162):ra12. https://doi.org/10.1126/scisignal.2001270 Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F (2011) ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal 4(162):ra12. https://​doi.​org/​10.​1126/​scisignal.​2001270
146.
Zurück zum Zitat Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4):1225–1232. https://doi.org/10.1182/blood-2006-12-064527CrossRefPubMed Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4):1225–1232. https://​doi.​org/​10.​1182/​blood-2006-12-064527CrossRefPubMed
151.
Zurück zum Zitat Lissoni P, Brivio F, Fumagalli L, Messina G, Meregalli S, Porro G, Rovelli F, Vigorè L, Tisi E, D’Amico G (2009) Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res 29(5):1847–1852PubMed Lissoni P, Brivio F, Fumagalli L, Messina G, Meregalli S, Porro G, Rovelli F, Vigorè L, Tisi E, D’Amico G (2009) Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res 29(5):1847–1852PubMed
154.
Zurück zum Zitat Greten TF, Ormandy LA, Fikuart A, Höchst B, Henschen S, Hörning M, Manns MP, Korangy F (2010) Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother (Hagerstown, Md : 1997) 33(2):211–218. https://doi.org/10.1097/CJI.0b013e3181bb499f Greten TF, Ormandy LA, Fikuart A, Höchst B, Henschen S, Hörning M, Manns MP, Korangy F (2010) Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother (Hagerstown, Md : 1997) 33(2):211–218. https://​doi.​org/​10.​1097/​CJI.​0b013e3181bb499f​
155.
Zurück zum Zitat Generali D, Bates G, Berruti A, Brizzi MP, Campo L, Bonardi S, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Banham AH, Harris AL, Bottini A, Fox SB (2009) Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin Cancer Res 15(3):1046–1051. https://doi.org/10.1158/1078-0432.ccr-08-1507CrossRefPubMed Generali D, Bates G, Berruti A, Brizzi MP, Campo L, Bonardi S, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Banham AH, Harris AL, Bottini A, Fox SB (2009) Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin Cancer Res 15(3):1046–1051. https://​doi.​org/​10.​1158/​1078-0432.​ccr-08-1507CrossRefPubMed
157.
Zurück zum Zitat Patel MA, Kim JE, Theodros D, Tam A, Velarde E, Kochel CM, Francica B, Nirschl TR, Ghasemzadeh A, Mathios D, Harris-Bookman S, Jackson CC, Jackson C, Ye X, Tran PT, Tyler B, Coric V, Selby M, Brem H, Drake CG, Pardoll DM, Lim M (2016) Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. J Immunother Cancer 4:28. https://doi.org/10.1186/s40425-016-0132-2CrossRefPubMedPubMedCentral Patel MA, Kim JE, Theodros D, Tam A, Velarde E, Kochel CM, Francica B, Nirschl TR, Ghasemzadeh A, Mathios D, Harris-Bookman S, Jackson CC, Jackson C, Ye X, Tran PT, Tyler B, Coric V, Selby M, Brem H, Drake CG, Pardoll DM, Lim M (2016) Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. J Immunother Cancer 4:28. https://​doi.​org/​10.​1186/​s40425-016-0132-2CrossRefPubMedPubMedCentral
158.
168.
172.
Zurück zum Zitat Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V, Zuercher WJ, Powell JD, Shinohara ML, McDonnell DP, Rathmell JC (2011) Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A 108(45):18348–18353. https://doi.org/10.1073/pnas.1108856108CrossRefPubMedPubMedCentral Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V, Zuercher WJ, Powell JD, Shinohara ML, McDonnell DP, Rathmell JC (2011) Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A 108(45):18348–18353. https://​doi.​org/​10.​1073/​pnas.​1108856108CrossRefPubMedPubMedCentral
179.
Zurück zum Zitat Rotin D, Robinson B, Tannock IF (1986) Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors. Cancer Res 46(6):2821–2826PubMed Rotin D, Robinson B, Tannock IF (1986) Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors. Cancer Res 46(6):2821–2826PubMed
181.
Metadaten
Titel
Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment
verfasst von
Varun Sasidharan Nair
Reem Saleh
Salman M. Toor
Farhan S. Cyprian
Eyad Elkord
Publikationsdatum
03.02.2021
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 8/2021
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-020-02842-y

Weitere Artikel der Ausgabe 8/2021

Cancer Immunology, Immunotherapy 8/2021 Zur Ausgabe

Adjuvante Immuntherapie verlängert Leben bei RCC

25.04.2024 Nierenkarzinom Nachrichten

Nun gibt es auch Resultate zum Gesamtüberleben: Eine adjuvante Pembrolizumab-Therapie konnte in einer Phase-3-Studie das Leben von Menschen mit Nierenzellkarzinom deutlich verlängern. Die Sterberate war im Vergleich zu Placebo um 38% geringer.

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

25.04.2024 NSCLC Nachrichten

Das Risiko für Rezidiv oder Tod von Patienten und Patientinnen mit reseziertem ALK-positivem NSCLC ist unter einer adjuvanten Therapie mit dem Tyrosinkinase-Inhibitor Alectinib signifikant geringer als unter platinbasierter Chemotherapie.

Bei Senioren mit Prostatakarzinom auf Anämie achten!

24.04.2024 DGIM 2024 Nachrichten

Patienten, die zur Behandlung ihres Prostatakarzinoms eine Androgendeprivationstherapie erhalten, entwickeln nicht selten eine Anämie. Wer ältere Patienten internistisch mitbetreut, sollte auf diese Nebenwirkung achten.

ICI-Therapie in der Schwangerschaft wird gut toleriert

Müssen sich Schwangere einer Krebstherapie unterziehen, rufen Immuncheckpointinhibitoren offenbar nicht mehr unerwünschte Wirkungen hervor als andere Mittel gegen Krebs.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.