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Volume 9
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10.3390/cells9071581
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Article

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo

by
Sebastian J. Schober
1,*,
Melanie Thiede
1,
Hendrik Gassmann
1,
Carolin Prexler
1,
Busheng Xue
1,
David Schirmer
1,
Dirk Wohlleber
2,
Stefanie Stein
3,
Thomas G. P. Grünewald
3,4,5,
Dirk H. Busch
6,
Guenther H. S. Richter
1,7,
Stefan E. G. Burdach
1,8 and
Uwe Thiel
1,*
1
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
2
Institute of Molecular Immunology/Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, 81674 Munich, Germany
3
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU, 80337 Munich, Germany
4
Division of Translational Pediatric Sarcoma Research, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
5
Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
6
Institute for Medical Microbiology, Immunology and Hygiene, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81674 Munich, Germany
7
Division of Oncology and Hematology, Department of Pediatrics, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
8
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), partner site Munich, 80336 Munich, Germany
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(7), 1581; https://doi.org/10.3390/cells9071581
Received: 31 May 2020 / Revised: 23 June 2020 / Accepted: 26 June 2020 / Published: 29 June 2020
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
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Abstract

In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4+ T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4+ T cell populations to their CD8+ counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP130-TCR transgenic (tg) CD4+ versus CD8+ T cells in tumor-bearing xenografted Rag2−/−γc−/− mice. TCR tgCD4+ T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8+ cells after 5–6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8+ cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4+ T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS. View Full-Text
Keywords: adoptive T cell transfer; CD4+ T cells; allorepertoire-derived TCR; Ewing sarcoma adoptive T cell transfer; CD4+ T cells; allorepertoire-derived TCR; Ewing sarcoma
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MDPI and ACS Style

Schober, S.J.; Thiede, M.; Gassmann, H.; Prexler, C.; Xue, B.; Schirmer, D.; Wohlleber, D.; Stein, S.; Grünewald, T.G.P.; Busch, D.H.; Richter, G.H.S.; Burdach, S.E.G.; Thiel, U. MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo. Cells 2020, 9, 1581. https://doi.org/10.3390/cells9071581

AMA Style

Schober SJ, Thiede M, Gassmann H, Prexler C, Xue B, Schirmer D, Wohlleber D, Stein S, Grünewald TGP, Busch DH, Richter GHS, Burdach SEG, Thiel U. MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo. Cells. 2020; 9(7):1581. https://doi.org/10.3390/cells9071581

Chicago/Turabian Style

Schober, Sebastian J., Melanie Thiede, Hendrik Gassmann, Carolin Prexler, Busheng Xue, David Schirmer, Dirk Wohlleber, Stefanie Stein, Thomas G.P. Grünewald, Dirk H. Busch, Guenther H.S. Richter, Stefan E.G. Burdach, and Uwe Thiel. 2020. "MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo" Cells 9, no. 7: 1581. https://doi.org/10.3390/cells9071581

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