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Review

Blockade of TGF-β signaling: a potential target for cancer immunotherapy?

Pages 679-693 | Received 15 Apr 2019, Accepted 21 Jun 2019, Published online: 27 Jun 2019

References

  • Flavell RA, Sanjabi S, Wrzesinski SH, et al. The polarization of immune cells in the tumour environment by TGFβ. Nat Rev Immunol. 2010;10:554–567.
  • Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32:51–82.
  • Yang Z, Mu Z, Dabovic B, et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice. J Cell Biol. 2007;176:787–793.
  • Travis MA, Reizis B, Melton AC, et al. Loss of integrin α(v)β8 on dendritic cells causes autoimmunity and colitis in mice. Nature. 2007;449:361–365.
  • Worthington JJ, Czajkowska BI, Melton AC, et al. Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8. Gastroenterology. 2011;141:1802–1812.
  • Edwards JP, Thornton AM, Shevach EM. Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8. J Immunol. 2014;193:2843–2849.
  • Worthington JJ, Kelly A, Smedley C, et al. Integrin αvβ8-mediated TGF-β activation by effector regulatory T cells is essential for suppression of T-cell-mediated inflammation. Immunity. 2015;42:903–915.
  • Mu Y, Gudey SK, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res. 2012;347(1):11–20.
  • David CJ, Massague J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018;19(7):479.
  • Ayyaz A, Attisano L, Wrana JL. Recent advances in understanding contextual TGFβ signaling. F1000Res. 2017;6:749.
  • Ungefroren H. TGF-β signaling in cancer: control by negative regulators and crosstalk with proinflammatory and fibrogenic pathways. Cancers (Basel). 2019;11(3):E384.
  • Massague J. TGFβ in Cancer. Cell. 2008;134:215–230.
  • Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer. 2017;3:56–71.
  • Seoane J. Escaping from the TGFβ anti-proliferative control. Carcinogenesis. 2006;27(11):2148–2156.
  • Tian M, Neil JR, Schiemann WP. Transforming growth factor-β and the hallmarks of cancer. Cell Signal. 2011;23:951–962.
  • Calon A, Lonardo E, Berenguer-Llergo A. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47:320–329.
  • Calon A, Espinet E, Palomo-Ponce S, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–584.
  • Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964.
  • Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity. 2018;48:812–830.
  • Sanjabi S, Oh SA, Li MO. Regulation of the immune response by TGF-β: from conception to autoimmunity and infection. Cold Spring Harb Perspect Biol. 2017;9:a022236.
  • Dahmani A, Delisle JS. TGF-β in T cell biology: implications for cancer immunotherapy. Cancers (Basel). 2018;10(6):E194.
  • Ouyang W, Beckett O, Ma Q, et al. Transforming growth factor-β signaling curbs thymic negative selection promoting regulatory T cell development. Immunity. 2010;32:642–653.
  • Gorelik L, Flavell RA. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12:171–181.
  • Sanjabi S, Mosaheb MM, Flavell RA. Opposing effects of TGF-β and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity. 2009;31:131–144.
  • Filippi CM, Juedes AE, Oldham JE, et al. Transforming growth factor-β suppresses the activation of CD8+ T-cells when naive but promotes their survival and function once antigen experienced: A two-faced impact on autoimmunity. Diabetes. 2008;57:2684–2692.
  • Guan T, Dominguez CX, Amezquita RA, et al. ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8(+) T cell fates. J Exp Med. 2018;215:1153–1168.
  • Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–548.
  • Patel SA, Meyer JR, Greco SJ, et al. Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. J Immunol. 2010;184(10):5885–5894.
  • Kuczek DE, Larsen AMH, Thorseth ML, et al. Collagen density regulates the activity of tumor-infiltrating T cells. J Immunother Cancer. 2019;7(1):68.
  • Kehrl JH, Wakefield LM, Roberts AB, et al. Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986;163:1037–1050.
  • Donkor MK, Sarkar A, Li MO. TGF-β1 produced by activated CD4(+) T cells antagonizes T cell surveillance of tumor development. Oncoimmunology. 2012;1:162–171.
  • Shi C, Chen Y, Chen Y, et al. CD4+ CD25+ regulatory T cells promote hepatocellular carcinoma invasion via TGF-β1-induced epithelial-mesenchymal transition. Onco Targets Ther. 2018;12:279–289.
  • Gorelik L, Fields PE, Flavell RA. Cutting edge: TGF-β inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol. 2000;165:4773–4777.
  • Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation. J Exp Med. 2002;195:1499–1505.
  • Lin JT, Martin SL, Xia L, et al. TGF-β 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol. 2005;174:5950–5958.
  • Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–1886.
  • Fantini MC, Becker C, Monteleone G, et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004;172:5149–5153.
  • Liu Y, Zhang P, Li J, et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol. 2008;9:632–640.
  • Liénart S, Merceron R, Vanderaa C, et al. Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells. Science. 2018;362(6417):952–956.
  • Cuende J, Liénart S, Dedobbeleer O, et al. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med. 2015;7(284):284ra56.
  • Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012;3:51.
  • Chaput N, Louafi S, Bardier A, et al. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut. 2009;58:520–529.
  • Wang A, Pan D, Lee YH, et al. Cutting edge: smad2 and Smad4 regulate TGF-β-mediated IL9 gene expression via EZH2 displacement. J Immunol. 2013;191(10):4908–4912.
  • Zhang S. The role of transforming growth factor β in T helper 17 differentiation. Immunology. 2018 Sep;155(1):24–35.
  • Skon CN, Lee JY, Anderson KG, et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat Immunol. 2013;14(12):1285–1293.
  • Mackay LK, Wynne-Jones E, Freestone D, et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity. 2015;43(6):1101–1111.
  • Zhou L, Lopes JE, Chong MM, et al. TGF-β-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453:236–240.
  • Hasan M, Neumann B, Haupeltshofer S, et al. Activation of TGF-β-induced non-Smad signaling pathways during Th17 differentiation. Immunol Cell Biol. 2015;93:662–672.
  • Hahn JN, Falck VG, Jirik FR. Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice. J Clin Investig. 2011;121:4030–4042.
  • Zhang S, Takaku M, Zou L, et al. Reversing SKI-SMAD4-mediated suppression is essential for Th17 cell differentiation. Nature. 2017;551:105–109.
  • Takai S, Schlom J, Tucker J, et al. Inhibition of TGF-β1 signaling promotes central memory T cell differentiation. J Immunol. 2013;191(5):2299–2307.
  • Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133.
  • Lucas PJ, Kim SJ, Melby SJ, et al. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor β II receptor. J Exp Med. 2000;191:1187–1196.
  • Zhang N, Bevan MJ. TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat Immunol. 2012;13:667–673.
  • Wolfraim LA, Walz TM, James Z, et al. p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-β-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol. 2004;173:3093–3102.
  • Li L, Iwamoto Y, Berezovskaya A, et al. A pathway regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3 is involved in the induction of T cell tolerance. Nat Immunol. 2006;7:1157–1165.
  • Ruegemer JJ, Ho SN, Augustine JA, et al. Regulatory effects of transforming growth factor-β on IL-2- and IL-4-dependent T cell-cycle progression. J Immunol. 1990;144:1767–1776.
  • Yang X, Letterio JJ, Lechleider RJ, et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. Embo J. 1999;18:1280–1291.
  • Delisle JS, Giroux M, Boucher G, et al. The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells. Genes Immun. 2013;14:115–126.
  • McKarns SC, Schwartz RH. Distinct effects of TGF-β 1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: A role for T cell intrinsic Smad3. J Immunol. 2005;174:2071–2083.
  • Chen CH, Seguin-Devaux C, Burke NA, et al. Transforming growth factor β blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med. 2003;197:1689–1699.
  • Park BV, Freeman ZT, Ghasemzadeh A, et al. TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discov. 2016;6:1366–1381.
  • Choudhry MA, Sir O, Sayeed MM. TGF-β abrogates TCR-mediated signaling by upregulating tyrosine phosphatases in T cells. Shock. 2001;15:193–199.
  • Giroux M, Delisle JS, O’Brien A, et al. T cell activation leads to protein kinase C theta-dependent inhibition of TGF-β signaling. J Immunol. 2010;185:1568–1576.
  • Arumugam V, Bluemn T, Wesley E, et al. TCR signaling intensity controls CD8+ T cell responsiveness to TGF-β. J Leukoc Biol. 2015;98(5):703–712.
  • Cottrez F, Groux H. Regulation of TGF-β response during T cell activation is modulated by IL-10. J Immunol. 2001;167:773–778.
  • Thomas DA, Massague J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369–380.
  • Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat Med. 2001;7:1118–1122.
  • Ahmadzadeh M, Rosenberg SA. TGF-β1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol. 2005;174:5215–5223.
  • Lin R, Chen L, Chen G, et al. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Investig. 2014;124:5352–5367.
  • Komdeur FL, Prins TM, van de Wall S, et al. CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer. OncoImmunology. 2017;6(9):e1338230.
  • Djenidi F, Adam J, Goubar A, et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol. 2015;194(7):3475–3486.
  • Zloza A, Jagoda MC, Lyons GE, et al. CD8 co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression. Cancer Immunol Immunother. 2011;60(2):291–297.
  • Casetti R, Agrati C, Wallace M, et al. Cutting edge: TGF-β1 and IL-15 Induce FOXP3+ gammadelta regulatory T cells in the presence of antigen stimulation. J Immunol. 2009;183:3574–3577.
  • Li X, Kang N, Zhang X, et al. Generation of human regulatory gammadelta T cells by TCRgammadelta stimulation in the presence of TGF-β and their involvement in the pathogenesis of systemic lupus erythematosus. J Immunol. 2011;86(12):6693–6700.
  • Doisne JM, Bartholin L, Yan KP, et al. iNKT cell development is orchestrated by different branches of TGF-beta signaling. J Exp Med. 2009;206:1365–1378.
  • Havenar-Daughton C, Li S, Benlagha K, et al. Development and function of murine RORgammat+ iNKT cells are under TGF-beta signaling control. Blood. 2012;119:3486–3494.
  • Konkel JE, Maruyama T, Carpenter AC, et al. Control of the development of CD8alphaalpha+ intestinal intraepithelial lymphocytes by TGF-beta. Nat Immunol. 2011;12:312–319.
  • Viel S, Marcais A, Guimaraes FS, et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9:ra19.
  • Castriconi R, Cantoni C, Della Chiesa M, et al. Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA. 2003;100:4120–4125.
  • Trotta R, Dal Col J, Yu J, et al. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol. 2008;181:3784–3792.
  • Marcoe JP, Lim JR, Schaubert KL, et al. TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol. 2012;13(9):843–850.
  • Gao Y, Souza-Fonseca-Guimaraes F, Bald T, et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat Immunol. 2017;18:1004–1015.
  • Cortez VS, Cervantes-Barragan L, Robinette ML, et al. Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands. Immunity. 2016;44:1127–1139.
  • Otegbeye F, Ojo E, Moreton S. Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models. PLoS One. 2018;13(1):e0191358.
  • Novitskiy SV, Pickup MW, Chytil A, et al. Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties. J Leukoc Biol. 2012;92:641–651.
  • Jung NC, Lee JH, Chung KH, et al. Dendritic cell-based immunotherapy for solid tumors. Transl Oncol. 2018;11(3):686–690.
  • Melton AC, Bailey-Bucktrout SL, Travis MA, et al. Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J Clin Investig. 2010;120:4436–4444.
  • Barilla RM, Diskin B, Caso RC, et al. Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma. Nat Commun. 2019;10(1):1424.
  • Draghiciu O, Lubbers J, Nijman HW, et al. Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology. 2015;4(1):e954829.
  • Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–194.
  • Peng J, Tsang JY, Li D, et al. Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages. Cancer Lett. 2013;331(2):239–249.
  • Jayaraman P, Parikh F, Newton JM, et al. TGF-β1 programmed myeloid-derived suppressor cells (MDSC) acquire immune-stimulating and tumor killing activity capable of rejecting established tumors in combination with radiotherapy. Oncoimmunology. 2018;7(10):e1490853.
  • Gonzalez-Junca A, Driscoll KE, Pellicciotta I, et al. Autocrine TGFβ is a survival factor for monocytes and drives immunosuppressive lineage commitment. Cancer Immunol Res. 2019;7(2):306–320.
  • Diebold RJ, Eis MJ, Yin M, et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA. 1995;92(26):12215–12219.
  • Nakamura S, Yaguchi T, Kawamura N, et al. TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression. J Immunother. 2014;37(2):63–72.
  • Donkor MK, Sarkar A, Savage PA, et al. T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine. Immunity. 2011;35:123–134.
  • Takasaka N, Seed RI, Cormier A, et al. Integrin αvβ8-expressing tumor cells evade host immunity by regulating TGF-β activation in immune cells. JCI Insight. 2018;3(20):122591.
  • Díaz-Valdés N, Basagoiti M, Dotor J, et al. Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Cancer Res. 2011;71(3):812–821.
  • Gil-Guerrero L, Dotor J, Huibregtse IL, et al. In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1. J Immunol. 2008;181(1):126–135.
  • Zhang L, Yu Z, Muranski P, et al. Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther. 2013;20(5):575–580.
  • Zhang Q, Yang X, Pins M, et al. Adoptive transfer of tumor-reactive transforming growth factor-β-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res. 2005;65:1761–1769.
  • Foster AE, Dotti G, Lu A, et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-β receptor. J Immunother. 2008;31:500–505.
  • Wang L, Wen W, Yuan J, et al. Immunotherapy for human renal cell carcinoma by adoptive transfer of autologous transforming growth factor β-insensitive CD8+ T cells. Clin Cancer Res. 2010;16:164–173.
  • Kloss CC, Lee J, Zhang A, et al. Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26(7):1855–1866.
  • Zhang Q, Helfand BT, Carneiro BA, et al. Efficacy against human prostate cancer by prostate-specific membrane antigen-specific, transforming growth factor-β insensitive genetically targeted CD8(+) T-cells derived from patients with metastatic castrate-resistant disease. Eur Urol. 2018;73:648–652.
  • Bollard CM, Tripic T, Cruz CR, et al. Tumor-specific T-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed hodgkin lymphoma. J Clin Oncol. 2018;36:1128–1139.
  • Principe DR, DeCant B, Mascariñas E, et al. TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res. 2016;76(9):2525–2539.
  • Uhl M, Aulwurm S, Wischhusen J, et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res. 2004;64(21):7954–7961.
  • Yoon JH, Jung SM, Park SH, et al. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Mol Med. 2013;5(11):1720–1739.
  • Hanks BA, Holtzhausen A, Evans KS, et al. Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest. 2013;123(9):3925–3940.
  • Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–543.
  • Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014;5(article):5241.
  • Sow HS, Ren J, Camps M, et al. Combined inhibition of TGF-β signaling and the PD-L1 immune checkpoint is differentially effective in tumor models. Cells. 2019;8(4):E320.
  • Holmgaard RB, Schaer DA, Li Y, et al. Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. J Immunother Cancer. 2018;6(1):47.
  • Löffek S. Transforming of the tumor microenvironment: implications for TGF-β inhibition in the context of immune-checkpoint therapy. J Oncol. 2018;2018:9732939.
  • Garrison K, Hahn T, Lee WC, et al. The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis. Cancer Immunol Immunother. 2012;61:511–521.
  • Park J, Wrzesinski SH, Stern E, et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat Mater. 2012;11:895–905.
  • Hutzen B, Chen CY, Wang PY, et al. TGF-β inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma. Mol Ther Oncolytics. 2017;7:17–26.
  • Courau T, Nehar-Belaid D, Florez L, et al. TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies. JCI Insight. 2016;1:e85974.
  • Terabe M, Ambrosino E, Takaku S, et al. Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-β monoclonal antibody. Clin Cancer Res. 2009;15:6560–6569.
  • Kim S, Buchlis G, Fridlender ZG, et al. Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy. Cancer Res. 2008;68(24):10247–10256.
  • Ueda R, Fujita M, Zhu X, et al. Systemic inhibition of transforming growth factor-β in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin Cancer Res. 2009;15:6551–6559.
  • Takaku S, Terabe M, Ambrosino E, et al. Blockade of TGF-β enhances tumor vaccine efficacy mediated by CD8(+) T cells. Int J Cancer. 2010;126:1666–1674.
  • Xu Z, Wang Y, Zhang L, et al. Nanoparticle-delivered transforming growth factor-β siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano. 2014;8:3636–3645.
  • Terabe M, Robertson FC, Clark K, et al. Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. Oncoimmunology. 2017;6:e1308616.
  • Soares KC, Rucki AA, Kim V, et al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget. 2015;6(40):43005–43015.
  • Pu N, Zhao G, Yin H, et al. CD25 and TGF-β blockade based on predictive integrated immune ratio inhibits tumor growth in pancreatic cancer. J Transl Med. 2018;16(1):294.
  • Oettle H, Hilbig A, Seufferlein T, et al. Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen. J Clin Oncol. 2012;30(15_suppl):4034.
  • Bogdahn U, Hau P, Stockhammer G, et al. Targeted therapy or high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 2010;13(1):132–142.
  • Morris JC, Tan AR, Olencki TE, et al. Phase I study of GC1008 (Fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS ONE. 2014;9(3):e90353.
  • Ikeda M, Takahashi H, Kondo S, et al. Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2017;79(6):1169–1177.
  • Nizard M, Roussel H, Diniz MO, et al. Induction of resident memory T cells enhances the efficacy of cancer vaccine. Nat Commun. 2017;8:15221.
  • Fujii R, Jochems C, Tritsch SR, et al. An IL-15 superagonist/IL-15Rα fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression. Cancer Immunol Immunother. 2018;67(4):675–689.
  • Zhu C, Shen H, Zhu L, et al. Plasminogen activator inhibitor 1 promotes immunosuppression in human non-small cell lung cancers by enhancing TGF-Β1 expression in macrophage. Cell Physiol Biochem. 2017;44(6):2201–2211.
  • Zhu Y, Richardson JA, Parada LF, et al. Smad3 mutant mice develop metastatic colorectal cancer. Cell. 1998;94:703–714.
  • Strauss J, Heery CR, Schlom J, et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin Cancer Res. 2018;24(6):1287–1295.
  • Tang H, Wang Y, Chlewicki L, et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016;30(3):500.
  • Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–1022.
  • Chakravarthy A, Khan L, Bensler NP, et al. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun. 2018;9(1):4692.

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