Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via notch signaling

Yangbing Zhao, Maria R. Parkhurst, Zhili Zheng, Cyrille J. Cohen, John P. Riley, Luca Gattinoni, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticle

Abstract

Adoptive cell transfer (ACT) of tumor-reactive lymphocytes has been shown to be an effective treatment for cancer patients. Studies in murine models of ACT indicated that antitumor efficacy of adoptively transferred T cells is dependent on the differentiation status of the cells, with lymphocyte differentiation inversely correlated with in vivo antitumor effectiveness. T-cell in vitro development technologies provide a new opportunity to generate naive T cells for the purpose of ACT. In this study, we genetically modified human umbilical cord blood-derived hematopoietic stem cells (HSCs) to express tumor antigen-specific T-cell receptor (TCR) genes and generated T lymphocytes by coculture with a murine cell line expressing Notch-1 ligand, Delta-like-1 (OP9-DL1). Input HSCs were differentiated into T cells as evidenced by the expression of T-cell markers, such as CD7, CD1a, CD4, CD8, and CD3, and by detection of TCR excision circles. We found that such in vitro differentiated T cells expressed the TCR and showed HLA-A2-restricted, specific recognition and killing of tumor antigen peptide-pulsed antigen-presenting cells but manifested additional natural killer cell-like killing of tumor cell lines. The genetic manipulation of HSCs has broad implications for ACT of cancer.

Original languageEnglish (US)
Pages (from-to)2425-2429
Number of pages5
JournalCancer Research
Volume67
Issue number6
DOIs
StatePublished - Mar 15 2007
Externally publishedYes

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Hematopoietic Stem Cells
Adoptive Transfer
T-Lymphocytes
Neoplasms
Neoplasm Antigens
T-Cell Antigen Receptor
Lymphocytes
HLA-A2 Antigen
T-Cell Receptor Genes
Antigen-Presenting Cells
Coculture Techniques
Tumor Cell Line
Fetal Blood
Natural Killer Cells
Cell Differentiation
Ligands
Technology
Cell Line
Peptides

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zhao, Y., Parkhurst, M. R., Zheng, Z., Cohen, C. J., Riley, J. P., Gattinoni, L., ... Morgan, R. A. (2007). Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via notch signaling. Cancer Research, 67(6), 2425-2429. https://doi.org/10.1158/0008-5472.CAN-06-3977

Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via notch signaling. / Zhao, Yangbing; Parkhurst, Maria R.; Zheng, Zhili; Cohen, Cyrille J.; Riley, John P.; Gattinoni, Luca; Restifo, Nicholas P.; Rosenberg, Steven A.; Morgan, Richard A.

In: Cancer Research, Vol. 67, No. 6, 15.03.2007, p. 2425-2429.

Research output: Contribution to journalArticle

Zhao, Y, Parkhurst, MR, Zheng, Z, Cohen, CJ, Riley, JP, Gattinoni, L, Restifo, NP, Rosenberg, SA & Morgan, RA 2007, 'Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via notch signaling', Cancer Research, vol. 67, no. 6, pp. 2425-2429. https://doi.org/10.1158/0008-5472.CAN-06-3977
Zhao, Yangbing ; Parkhurst, Maria R. ; Zheng, Zhili ; Cohen, Cyrille J. ; Riley, John P. ; Gattinoni, Luca ; Restifo, Nicholas P. ; Rosenberg, Steven A. ; Morgan, Richard A. / Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via notch signaling. In: Cancer Research. 2007 ; Vol. 67, No. 6. pp. 2425-2429.
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