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 language | English (US) |
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Article number | 17 |
Pages (from-to) | 811-827 |
Number of pages | 17 |
Journal | Cell transplantation |
Volume | 25 |
Issue number | 5 |
DOIs | |
State | Published - 2016 |
Funding
This project was funded, in part, under grants with the National Institute of Health Grant R21AI109239 and K18CA151798, Leona M. and Harry B. Helmsley Charitable Trust 2014PG-T1D049, and the Pennsylvania Department of Health using Tobacco Settlement Fund SAP #4100057673 to J.S. The authors declare no conflicts of interest.
Keywords
- Adoptive transfer
- Experimental immunotherapy
- Genetic modification
- Mouse
- Pluripotent stem cells
- T cells
ASJC Scopus subject areas
- Biomedical Engineering
- Cell Biology
- Transplantation