Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells.
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.
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
Tong
T
Zhang
Charles L
CL
Sentman
D000818:Animals; D001681:Biological Assay; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000276:immunology; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000276:immunology; D009389:Neovascularization, Pathologic; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000276:immunology; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000276:immunology; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D012190:Retroviridae; D012878:Skin Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C527086:Klrk1 protein, mouse; D050506:Mutant Chimeric Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D052899:Pore Forming Cytotoxic Proteins; C490521:Rae1 protein, mouse; C483886:perforin, mouse; D007371:Interferon-gamma