Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57

Oncotarget. 2015 Jan 1;6(1):171-84. doi: 10.18632/oncotarget.2767.

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.

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / metabolism*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • CD57 Antigens / metabolism*
  • CD8-Positive T-Lymphocytes / cytology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Flow Cytometry
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Glycoproteins / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology
  • Peptides / metabolism*
  • Receptors, Antigen / metabolism
  • T-Lymphocytes / immunology
  • Up-Regulation

Substances

  • AC133 Antigen
  • Antigens, CD
  • CD57 Antigens
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • Receptors, Antigen