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

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Cells
• Subjects: adoptive T cell transfer; CD4⁺ T cells; allorepertoire-derived TCR; Ewing sarcoma
• Online Access: https://www.mdpi.com/2073-4409/9/7/1581
• ISSN: 2073-4409

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<i> six transmembrane epithelial antigen of the prostate 1</i> (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^-/-gc^-/-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.