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

Schober, Sebastian J.; Thiede, Melanie; Gassmann, Hendrik; Prexler, Carolin; Xue, Busheng; Schirmer, David; Wohlleber, Dirk; Stein, Stefanie; Grunewald, Thomas G. P.; Busch, Dirk H.; Richter, Guenther H. S.; Burdach, Stefan E. G. und Thiel, Uwe (2020): MHC Class I-Restricted TCR-Transgenic CD4(+)T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo. In: Cells, Bd. 9, Nr. 7, 1581

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 fromsix 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 STEAP(130)-TCR transgenic (tg) CD4(+)versus CD8(+)T cells in tumor-bearing xenografted Rag2(-/-)gamma c(-/-)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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch