Abstract
Transforming growth factor β (TGF-β) is a cytokine with complex biological functions that may involve tumor promotion or tumor suppression. It has been reported that multiple types of tumors secrete TGF-β, which can inhibit tumor-specific cellular immunity and may represent a major obstacle to the success of tumor immunotherapy. In this study, we sought to enhance tumor immunotherapy using genetically modified antigen-specific T cells by interfering with TGF-β signaling. We constructed three γ-retroviral vectors, one that expressed TGF-β-dominant-negative receptor II (DNRII) or two that secreted soluble TGF-β receptors: soluble TGF-β receptor II (sRII) and the sRII fused with mouse IgG Fc domain (sRIIFc). We demonstrated that T cells genetically modified with these viral vectors were resistant to exogenous TGF-β-induced smad-2 phosphorylation in vitro. The functionality of antigen-specific T cells engineered to resist TGF-β signaling was further evaluated in vivo using the B16 melanoma tumor model. Antigen-specific CD8+ T cells (pmel-1) or CD4+ T cells (tyrosinase-related protein-1) expressing DNRII dramatically improved tumor treatment efficacy. There was no enhancement in the B16 tumor treatment using cells secreting soluble receptors. Our data support the potential application of the blockade of TGF-β signaling in tumor-specific T cells for cancer immunotherapy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298: 850–854.
Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17: 4550–4557.
Yingling JM, Blanchard KL, Sawyer JS . Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004; 3: 1011–1022.
Penafuerte C, Galipeau J . TGF beta secreted by B16 melanoma antagonizes cancer gene immunotherapy bystander effect. Cancer Immunol Immunother 2008; 57: 1197–1206.
Gorelik L, Flavell RA . Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2002; 2: 46–53.
Gorelik L, Constant S, Flavell RA . Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 2002; 195: 1499–1505.
Park K, Kim SJ, Bang YJ, Park JG, Kim NK, Roberts AB et al. Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci USA 1994; 91: 8772–8776.
Knaus PI, Lindemann D, DeCoteau JF, Perlman R, Yankelev H, Hille M et al. A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 1996; 16: 3480–3489.
Ebner R, Chen RH, Shum L, Lawler S, Zioncheck TF, Lee A et al. Cloning of a type I TGF-beta receptor and its effect on TGF-beta binding to the type II receptor. Science 1993; 260: 1344–1348.
Attisano L, Carcamo J, Ventura F, Weis FM, Massague J, Wrana JL . Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell 1993; 75: 671–680.
Ikushima H, Miyazono K . TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 2010; 10: 415–424.
Terabe M, Ambrosino E, Takaku S, O'Konek JJ, Venzon D, Lonning S et al. Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res 2009; 15: 6560–6569.
Gorelik L, Flavell RA . Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000; 12: 171–181.
Gorelik L, Flavell RA . Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001; 7: 1118–1122.
Bollard CM, Rossig C, Calonge MJ, Huls MH, Wagner HJ, Massague J et al. Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood 2002; 99: 3179–3187.
Foster AE, Dotti G, Lu A, Khalil M, Brenner MK, Heslop HE et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. J Immunother 2008; 31: 500–505.
Russo LM, Brown D, Lin HY . The soluble transforming growth factor-beta receptor: advantages and applications. Int J Biochem Cell Biol 2009; 41: 472–476.
Seth P, Wang ZG, Pister A, Zafar MB, Kim S, Guise T et al. Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor-beta receptor II and human immunoglobulin Fc for breast cancer therapy. Hum Gene Ther 2006; 17: 1152–1160.
Hu Z, Zhang Z, Guise T, Seth P . Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-beta receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum Gene Ther 2010; 21: 1623–1629.
Hu Z, Gerseny H, Zhang Z, Chen YJ, Berg A, Stock S et al. Oncolytic adenovirus expressing soluble TGFbeta receptor II-Fc-mediated inhibition of established bone metastases: a safe and effective systemic therapeutic approach for breast cancer. Mol Ther 2011; 19: 1609–1618.
Overwijk WW, Theoret MR, Finkelstein SE, Surman DR, de Jong LA, Vyth-Dreese FA et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 2003; 198: 569–580.
Kerkar SP, Sanchez-Perez L, Yang S, Borman ZA, Muranski P, Ji Y et al. Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies. J Immunother 2011; 34: 343–352.
Xie Y, Akpinarli A, Maris C, Hipkiss EL, Lane M, Kwon EK et al. Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med 2010; 207: 651–667.
Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008; 112: 362–373.
Huter EN, Stummvoll GH, DiPaolo RJ, Glass DD, Shevach EM . Cutting edge: antigen-specific TGF beta-induced regulatory T cells suppress Th17-mediated autoimmune disease. J Immunol 2008; 181: 8209–8213.
Cejas PJ, Walsh MC, Pearce EL, Han D, Harms GM, Artis D et al. TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood 2010; 115: 4750–4757.
Lu L, Wang J, Zhang F, Chai Y, Brand D, Wang X et al. Role of SMAD and non-SMAD signals in the development of Th17 and regulatory T cells. J Immunol 2010; 184: 4295–4306.
Muranski P, Restifo NP . Adoptive immunotherapy of cancer using CD4(+) T cells. Curr Opin Immunol 2009; 21: 200–208.
Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 2002; 109: 1551–1559.
Ruffini PA, Rivoltini L, Silvani A, Boiardi A, Parmiani G . Factors, including transforming growth factor beta, released in the glioblastoma residual cavity, impair activity of adherent lymphokine-activated killer cells. Cancer Immunol Immunother 1993; 36: 409–416.
Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman MK, Whitesell LJ et al. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003; 63: 1860–1864.
Rowland-Goldsmith MA, Maruyama H, Matsuda K, Idezawa T, Ralli M, Ralli S et al. Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis. Mol Cancer Ther 2002; 1: 161–167.
Suzuki E, Kapoor V, Cheung HK, Ling LE, DeLong PA, Kaiser LR et al. Soluble type II transforming growth factor-beta receptor inhibits established murine malignant mesothelioma tumor growth by augmenting host antitumor immunity. Clin Cancer Res 2004; 10: 5907–5918.
Bandyopadhyay A, Lopez-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J et al. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 2002; 62: 4690–4695.
Bandyopadhyay A, Wang L, Lopez-Casillas F, Mendoza V, Yeh IT, Sun L . Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer. Prostate 2005; 63: 81–90.
Ostroukhova M, Seguin-Devaux C, Oriss TB, Dixon-McCarthy B, Yang L, Ameredes BT et al. Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 2004; 114: 28–38.
Li H, Han Y, Guo Q, Zhang M, Cao X . Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 2009; 182: 240–249.
Hughes MS, Yu YY, Dudley ME, Zheng Z, Robbins PF, Li Y et al. Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. Hum Gene Ther 2005; 16: 457–472.
Wargo JA, Robbins PF, Li Y, Zhao Y, El-Gamil M, Caragacianu D et al. Recognition of NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and epigenetic modulation of tumor antigen expression. Cancer Immunol Immunother 2009; 58: 383–394.
Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 2010; 70: 6725–6734.
Acknowledgements
We thank Dr Lalage Wakefield for kindly providing TGF-β DNRII vector and help in explaining data. FACS laboratory and the TIL laboratory in the Surgery Branch, National Cancer Institute provide technical support and maintenance of tumor cells from patients. This work is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Gene Therapy website
Supplementary information
Rights and permissions
About this article
Cite this article
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 20, 575–580 (2013). https://doi.org/10.1038/gt.2012.75
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gt.2012.75
Keywords
This article is cited by
-
PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial
Nature Medicine (2022)
-
Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment
Cellular & Molecular Immunology (2021)
-
C-phycocyanin inhibits epithelial-to-mesenchymal transition in Caski cells
Cancer Cell International (2020)
-
Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system
Frontiers of Medicine (2020)
-
Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment
Journal for ImmunoTherapy of Cancer (2017)