title: Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57.
abstract: The AC133 epitope of CD133 is a cancer stem cell (CSC) marker for many tumor entities, including the highly malignant glioblastoma multiforme (GBM). We have developed an AC133-specific chimeric antigen receptor (CAR) and show that AC133-CAR T cells kill AC133+ GBM stem cells (GBM-SCs) both in vitro and in an orthotopic tumor model in vivo. Direct contact with patient-derived GBM-SCs caused rapid upregulation of CD57 on the CAR T cells, a molecule known to mark terminally or near-terminally differentiated T cells. However, other changes associated with terminal T cell differentiation could not be readily detected. CD57 is also expressed on tumor cells of neural crest origin and has been preferentially found on highly aggressive, undifferentiated, multipotent CSC-like cells. We found that CD57 was upregulated on activated T cells only upon contact with CD57+ patient-derived GBM-SCs, but not with conventional CD57-negative glioma lines. However, CD57 was not downregulated on the GBM-SCs upon their differentiation, indicating that this molecule is not a bona fide CSC marker for GBM. Differentiated GBM cells still induced CD57 on CAR T cells and other activated T cells. Therefore, CD57 can apparently be upregulated on activated human T cells by mere contact with CD57+ target cells.
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Xuekai
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Gaedicke
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hettich
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Firat
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D018959:CD57 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology; D010455:Peptides / Q000378:metabolism*; D011946:Receptors, Antigen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018959:CD57 Antigens; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011946:Receptors, Antigen