TY - JOUR
T1 - MHC class i-restricted TCR-transgenic CD4+ T cells against STEAP1 mediate local tumor control of ewing sarcoma in vivo
AU - Schober, Sebastian J.
AU - Thiede, Melanie
AU - Gassmann, Hendrik
AU - Prexler, Carolin
AU - Xue, Busheng
AU - Schirmer, David
AU - Wohlleber, Dirk
AU - Stein, Stefanie
AU - Grünewald, Thomas G.P.
AU - Busch, Dirk H.
AU - Richter, Guenther H.S.
AU - Burdach, Stefan E.G.
AU - Thiel, Uwe
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Adoptive T cell transfer
KW - Allorepertoire-derived TCR
KW - CD4 T cells
KW - Ewing sarcoma
UR - http://www.scopus.com/inward/record.url?scp=85087471413&partnerID=8YFLogxK
U2 - 10.3390/cells9071581
DO - 10.3390/cells9071581
M3 - Article
C2 - 32610710
AN - SCOPUS:85087471413
SN - 2073-4409
VL - 9
SP - 1
EP - 15
JO - Cells
JF - Cells
IS - 7
M1 - 1581
ER -