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Open AccessArticle

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

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)
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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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.

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