Antitumor Activity of EBV-specific T Lymphocytes Transduced With a Dominant Negative TGF-β Receptor
Open accessAbstract
Transforming growth factor (TGF)-beta is produced in most human tumors and markedly inhibits tumor antigen-specific cellular immunity, representing a major obstacle to the success of tumor immunotherapy. TGF-beta is produced in Epstein-Barr virus (EBV)-positive Hodgkin disease and non-Hodgkin lymphoma both by the tumor cells and by infiltrating T-regulatory cells and may contribute the escape of these tumors from infused EBV-specific T cells. To determine whether tumor antigen-specific cytotoxic T lymphocytes (CTLs) can be shielded from the inhibitory effects of tumor-derived TGF-beta, we previously used a hemagglutinin-tagged dominant negative TGF-betaRII expressed from a retrovirus vector to provide CTLs with resistance to the inhibitory effects of TGF-beta in vitro. We now show that human tumor antigen-specific CTLs can be engineered to resist the inhibitory effects of tumor-derived TGF-beta both in vitro and in vivo using a clinical grade retrovirus vector in which the dominant negative TGF-beta type II receptor (DNRII) was modified to remove the immunogenic hemagglutinin tag. TGF-beta-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-beta-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure.
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TGF-β acts as a potent immunostimulant of CAR-T cells engineered with a chimeric TGF-β-binding CAR, rather than exerting its normal immunosuppressive role.
“Thus, rather than exerting its normal immunosuppressive role, TGF-β acts as a potent immunostimulant of these CAR-T cells378,379.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [378]
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Cites
The Transforming Growth Factor-Beta Family
Massagué, J. (1990) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.06.110190.003121 · Cited by 3,041 · see citing works
Cancer regression in patients after transfer of genetically engineered lymphocytes
Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., Royal, R. E., Topalian, S. L., Kammula, U. S., Restifo, N. P., et al. (2006) · Science · doi:10.1126/science.1129003 · Cited by 2,603 · see citing works
TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders
Massagué, J., Blain, S. W., & Lo, R. S. (2000) · Cell · doi:10.1016/s0092-8674(00)00121-5 · Cited by 2,386 · see citing works
Immunosuppressive networks in the tumour environment and their therapeutic relevance
Zou, W. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1586 · Cited by 2,057 · see citing works
Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer
Siegel, P. M., & Massagué, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1208 · Cited by 1,600 · see citing works
Melanoma Cell Expression of Fas(Apo-1/CD95) Ligand: Implications for Tumor Immune Escape
Hahne, M., Rimoldi, D., Schröter, M., Romero, P. J., Schreier, M. H., French, L. E., Schneider, P., Bornand, T., Fontana, A., Liénard, D., et al. (1996) · Science · doi:10.1126/science.274.5291.1363 · Cited by 1,236 · see citing works
Adoptive immunotherapy for cancer: building on success
Gattinoni, L., Powell, D. J., Rosenberg, S. A., & Restifo, N. P. (2006) · Nature reviews. Immunology · doi:10.1038/nri1842 · Cited by 841 · see citing works
Post-Transplant Lymphoproliferative Disorders
Gottschalk, S. M., Rooney, C. M., & Heslop, H. E. (2004) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104727 · Cited by 490 · see citing works
Self-citationYang, Z., Novak, A. J., Stenson, M. J., Witzig, T. E., & Ansell, S. M. (2006) · Blood · doi:10.1182/blood-2005-08-3376 · Cited by 419 · see citing works
Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease
Bollard, C. M., Aguilar, L. K., Straathof, K. C. M., Gahn, B., Huls, M. H., Rousseau, A., Sixbey, J. W., Gresik, M. V., Carrum, G., Hudson, M. M., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040890 · Cited by 387 · see citing works
Self-citationStebbings, R., Findlay, L., Edwards, C., Eastwood, D., Bird, C., North, D., Mistry, Y., Dilger, P., Liefooghe, E., Cludts, I., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.5.3325 · Cited by 317 · cited 1× · see citing works
“Neutralization efforts using monoclonal antibodies targeting TGF-b and TGF-bRII(15) have been reported, but systemic inhibition of a multifactorial molecule and potent immune response modifier such as TGF-b will likely have unpredictable adverse consequences.(17) The alternative strategy of targeting the inhibition of…”
BackgroundBollard, C. M., Rössig, C., Calonge, M. J., Huls, M. H., Wagner, H.-J., Massagué, J., Brenner, M. K., Heslop, H. E., & Rooney, C. M. (2002) · Blood · doi:10.1182/blood.v99.9.3179 · Cited by 316 · see citing works
Self-citationBollard, C. M., Gottschalk, S. M., Leen, A. M., Weiss, H. L., Straathof, K. C. M., Carrum, G., Khalil, M., Wu, M., Huls, M. H., Chang, C.-C., et al. (2007) · Blood · doi:10.1182/blood-2007-05-091280 · Cited by 278 · see citing works
Self-citationSavoldo, B., Rooney, C. M., Stasi, A. D., et al. (2007) · Blood · doi:10.1182/blood-2006-11-059139 · Cited by 234 · see citing works
Self-citationWieser, R., Attisano, L., Wrana, J. L., & Massagué, J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.12.7239-7247.1993 · Cited by 222 · see citing works
Dual Role of Transforming Growth Factor β in Mammary Tumorigenesis and Metastatic Progression
Muraoka-Cook, R. S., Dumont, N., & Arteaga, C. L. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.937s.11.2 · Cited by 168 · see citing works
Zhang, Q., Yang, X. J., Pins, M., Javonovic, B., Kuzel, T. M., Kim, S., Parijs, L. V., Greenberg, N. M., Liu, V., Guo, Y., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3169 · Cited by 146 · see citing works
Immune escape mechanisms in Hodgkin’s disease
Poppema, S., Potters, M., Visser, L., et al. (1998) · Annals of Oncology · doi:10.1093/annonc/9.suppl_5.s21 · Cited by 106 · see citing works
Lacuesta, K., Buza, E. L., Hauser, H., et al. (2006) · Journal of Immunotherapy · doi:10.1097/01.cji.0000192104.24583.ca · Cited by 44 · see citing works
In vitro transformation of human B-cell follicular lymphoma cells by Epstein-Barr virus.
Smith, L. J., Braylan, R. C., Edmundson, K. B., et al. (1987) · PubMed · Cited by 13 · see citing works
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Targeting the TGFβ signalling pathway in disease
Akhurst, R. J., & Hata, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3810 · Cited by 1,466 · see citing works
Engineered T cells: the promise and challenges of cancer immunotherapy
Fesnak, A. D., June, C. H., & Levine, B. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.97 · Cited by 1,074 · see citing works
TGFβ biology in cancer progression and immunotherapy
Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
Kloss, C. C., Lee, J., Zhang, A., Chen, F., Melenhorst, J. J., Lacey, S. F., Maus, M. V., Fraietta, J. A., Zhao, Y., & June, C. H. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.05.003 · Cited by 648 · see citing works
CAR T cells: Continuation in a revolution of immunotherapy
Singh, A. K., & McGuirk, J. P. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30823-x · Cited by 303 · see citing works
Rewiring T-cell responses to soluble factors with chimeric antigen receptors
Chang, Z. L., Lorenzini, M. H., Chen, X., Tran, U., Bangayan, N. J., & Chen, Y. Y. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2565 · Cited by 259 · see citing works
Bollard, C. M., Tripic, T., Cruz, C. R., Dotti, G., Gottschalk, S., Torrano, V., Dakhova, O., Carrum, G., Ramos, C. A., Liu, H., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.74.3179 · Cited by 181 · see citing works
Self-citationTGF‐β–responsive CAR‐T cells promote anti‐tumor immune function
Hou, A. J., Chang, Z. L., Lorenzini, M. H., Zah, E., & Chen, Y. Y. (2018) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10097 · Cited by 106 · see citing works
Adoptive T-cell therapy for cancer: the era of engineered T cells
Bonini, C., & Mondino, A. (2015) · European Journal of Immunology · doi:10.1002/eji.201545552 · Cited by 93 · see citing works
Virus-Specific T Cells for the Immunocompromised Patient
Houghtelin, A., & Bollard, C. M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01272 · Cited by 90 · see citing works
Self-citationGenetically Modified T-Cell Therapy for Osteosarcoma: Into the Roaring 2020s
DeRenzo, C., & Gottschalk, S. (2020) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-43032-0_10 · Cited by 12 · see citing works
- Authors
- Foster, A. E., Dotti, G., Lu, A., Khalil, M., Brenner, M. K., Heslop, H. E., Rooney, C. M., & Bollard, C. M.
- Affiliations
- Houston Methodist (US)
- Corresponding author
- Foster, Aaron E.
- Dotti, Gianpietro
- Lu, An
- Khalil, Mariam
- Brenner, Malcolm K.
- Heslop, Helen E.
- Rooney, Cliona M.
- Bollard, Catherine M.
- ORCID
- Venue
- Journal of Immunotherapy
- Published
- 2008-06
- Volume
- 31
- Issue
- 5
- Pages
- 500-505
- ISSN
- 1524-9557 (ISSN-L)
- PMC
- PMC2745436
- OpenAlex
- W2009709218
- Cited by
- 210
- References
- 20
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 13 · 2021: 11 · 2020: 16 · 2019: 17 · 2018: 28 · 2017: 21 · 2016: 17 · 2015: 10 · 2014: 6 · 2013: 13 · 2012: 12
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Immunotherapy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01 CA94 237, P01CA094237, P50CA126752)
- National Center for Research Resources (RR 00188, K01RR000188, M01RR000188)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TGF-beta, EBV-specific cytotoxic T lymphocytes, Epstein-Barr virus, EBV-associated lymphoma, Hodgkin's disease, cancer immunotherapy, regulatory T cells, retroviral gene transfer, TGF-beta resistance, anticancer activity
- MeSH terms
- Animals, Herpesvirus 4, Human, Genes, Dominant, Humans, Neoplasms, T-Lymphocytes, Transforming Growth Factor beta, Receptors, Transforming Growth Factor beta, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice
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