Melanoma immunotherapy in mice using genetically engineered pluripotent stem cells

Mohammad Haque, Jianyong Song, Kristin Fino, Praneet Sandhu, Youfei Wang, Bing Ni, Deyu Fang, Jianxun Song*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Adoptive cell transfer (ACT) of antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) is a highly promising treatment for a variety of diseases. Naive or central memory T-cell-derived effector CTLs are optimal populations for ACT-based immunotherapy because these cells have a high proliferative potential, are less prone to apoptosis than terminally differentiated cells, and have the higher ability to respond to homeostatic cytokines. However, such ACT with T-cell persistence is often not feasible due to difficulties in obtaining sufficient cells from patients. Here we present that in vitro differentiated HSCs of engineered PSCs can develop in vivo into tumor Ag-specific naive CTLs, which efficiently suppress melanoma growth. Mouse-induced PSCs (iPSCs) were retrovirally transduced with a construct encoding chicken ovalbumin (OVA)-specific T-cell receptors (TCRs) and survival-related proteins (i.e., BCL-xL and survivin). The gene-transduced iPSCs were cultured on the delta-like ligand 1-expressing OP9 (OP9-DL1) murine stromal cells in the presence of murine recombinant cytokines (rFlt3L and rIL-7) for a week. These iPSC-derived cells were then intravenously adoptively transferred into recipient mice, followed by intraperitoneal injection with an agonist a-Notch 2 antibody and cytokines (rFlt3L and rIL-7). Two weeks later, naive OVA-specific CD8+ T cells were observed in the mouse peripheral lymphatic system, which were responsive to OVA-specific stimulation. Moreover, the mice were resistant to the challenge of B16-OVA melanoma induction. These results indicate that genetically modified stem cells may be used for ACT-based immunotherapy or serve as potential vaccines.

Original languageEnglish (US)
Article number17
Pages (from-to)811-827
Number of pages17
JournalCell transplantation
Volume25
Issue number5
DOIs
StatePublished - 2016

Keywords

  • Adoptive transfer
  • Experimental immunotherapy
  • Genetic modification
  • Mouse
  • Pluripotent stem cells
  • T cells

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

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