Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcoma in vitro and in vivo

OncoImmunology

Dirk H. Busch¹  Andreas Kirschner²  Melanie Thiede²  Günther H. S. Richter²  Stefan Burdach²  Uwe Thiel²  Rebeca Alba Rubio³  Thomas G. P. Grünewald³  Thomas Kirchner³ 

[1] Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München;Klinikum rechts der Isar, Technische Universität München;Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich;

关键词: allogeneic;    ewing sarcoma;    pappa;    pappalysin;    t cell therapy;    transgenic tcr;   

DOI  :  10.1080/2162402X.2016.1273301

来源: DOAJ

【 摘 要 】

Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin-like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e., IGF binding proteins (IGFBPs), thereby setting free IGFs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA is associated with various cancers. It is overexpressed and required for proliferation in ES. PAPPA also stimulates normal bone growth. We isolated HLA-A*02:01+/peptide-restricted T cells from A*02:01− healthy donors directed against PAPPA, generated by priming with A*02:01+ PAPPA peptide loaded dendritic cells. After TCR identification, retrovirally TCR transduced CD8+ T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2−/−γc−/− mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity toward HLA-A*02:01+/PAPPA+ ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2−/−γc−/− mice and in vivo engraftment in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells in contrast to controls. Tumors of treated mice revealed tumor-infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a first-rate target for TCR-based immunotherapy of ES.

【 授权许可】

Unknown