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Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells
Tong Zhang1, Charles L Sentman
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Abstract:
Tumor angiogenesis plays an important role in the development of solid tumors, and targeting the tumor vasculature has emerged as a strategy to prevent growth and progression of solid tumors. In this study, we show that murine tumor vasculature expresses Rae1, a ligand for a stimulatory NK receptor NKG2D. By genetic modification of T cells with an NKG2D-based chimeric Ag receptor, referred to as chNKG2D in which the NKG2D receptor is fused to the signaling domain of CD3ζ-chain, T cells were capable of targeting tumor vasculature leading to reduced tumor angiogenesis and tumor growth. This occurred even in tumors where the tumor cells themselves did not express NKG2D ligands. H5V, an endothelial cell line, expresses Rae1 and was lysed by chNKG2D-bearing T cells in a perforin-dependent manner. In vitro capillary tube formation was inhibited by chNKG2D T cells through IFN-γ and cell-cell contact mechanisms. The in vivo antiangiogenesis effects mediated by chNKG2D-bearing T cells at the tumor site were dependent on IFN-γ and perforin. These results provide a novel mechanism for NKG2D-based targeting of solid tumors.
Insights
Researchers engineered T cells to target tumor vasculature expressing Rae1, a ligand for NKG2D. This novel approach reduced tumor angiogenesis and growth, offering a new strategy for solid tumor treatment.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Tumor angiogenesis is crucial for solid tumor development.
- Targeting tumor vasculature is a promising anti-cancer strategy.
- Rae1, a ligand for NKG2D, is expressed on murine tumor vasculature.
Purpose of the Study:
- To investigate the potential of targeting tumor vasculature using NKG2D-based chimeric antigen receptors (chNKG2D).
- To evaluate the efficacy of chNKG2D-engineered T cells in reducing tumor angiogenesis and growth.
- To elucidate the mechanisms underlying chNKG2D-mediated anti-tumor effects.
Main Methods:
- Genetic modification of T cells to express NKG2D-based chimeric antigen receptors (chNKG2D).
- Assessment of chNKG2D T cell-mediated lysis of Rae1-expressing endothelial cells (H5V) in vitro.
- Evaluation of in vitro capillary tube formation inhibition by chNKG2D T cells.
- In vivo studies to assess anti-angiogenesis and tumor growth reduction in murine models.
- Analysis of the role of perforin, IFN-γ, and cell-cell contact in the observed effects.
Main Results:
- Engineered chNKG2D T cells effectively targeted Rae1-expressing tumor vasculature.
- chNKG2D T cells reduced tumor angiogenesis and tumor growth, even in tumors lacking NKG2D ligands on tumor cells.
- Rae1-expressing endothelial cells were lysed by chNKG2D T cells in a perforin-dependent manner.
- In vitro and in vivo anti-angiogenesis effects were mediated by IFN-γ and perforin.
Conclusions:
- NKG2D-based chimeric antigen receptor T cells provide a novel strategy for targeting tumor vasculature.
- This approach offers a new mechanism for treating solid tumors by inhibiting angiogenesis.
- The study highlights the potential of targeting Rae1 on tumor vasculature for cancer immunotherapy.
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