MHC Class I-Restricted TCR-Transgenic CD4<sup>+</sup> T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo
Sebastian J. Schober,
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,
Uwe Thiel
Affiliations
Sebastian J. Schober
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Melanie Thiede
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Hendrik Gassmann
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Carolin Prexler
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Busheng Xue
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
David Schirmer
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Dirk Wohlleber
Institute of Molecular Immunology/Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, 81674 Munich, Germany
Stefanie Stein
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU, 80337 Munich, Germany
Thomas G. P. Grünewald
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU, 80337 Munich, Germany
Dirk H. Busch
Institute for Medical Microbiology, Immunology and Hygiene, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81674 Munich, Germany
Guenther H. S. Richter
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Stefan E. G. Burdach
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
Uwe Thiel
Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany
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.
