title: An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo.
abstract: NKp30 is a natural cytotoxicity receptor that is expressed on NK cells and recognizes B7-H6, which is expressed on several types of tumors but few normal cells. To target effector T cells against B7-H6+ tumors, we developed several chimeric AgRs (CARs) based on NKp30, which contain the CD28- and/or CD3ζ-signaling domains with the transmembrane domains from CD3ζ, CD28, or CD8α. The data show that chimeric NKp30-expressing T cells responded to B7-H6+ tumor cells. The NKp30 CAR-expressing T cells produced IFN-γ and killed B7-H6 ligand-expressing tumor cells; this response was dependent upon ligand expression on target cells but not on MHC expression. PBMC-derived dendritic cells also express NKp30 ligands, including immature dendritic cells, and they can stimulate NKp30 CAR-bearing T cells to produce IFN-γ, but to a lesser extent. The addition of a CD28-signaling domain significantly enhanced the activity of the NKp30 CAR in a PI3K-dependent manner. Adoptive transfer of T cells expressing a chimeric NKp30 receptor containing a CD28-signaling domain inhibited the growth of a B7-H6-expressing murine lymphoma (RMA/B7-H6) in vivo. Moreover, mice that remained tumor-free were resistant to a subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor Ags. Overall, this study demonstrates the specificity and therapeutic potential of adoptive immunotherapy with NKp30 CAR-expressing T cells against B7-H6+ tumor cells in vivo.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Ming-Ru
authors.initials: MR
authors.lastname: Wu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D060887:B7 Antigens / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016923:Cell Death / Q000276:immunology; D005770:Gastrointestinal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020298:U937 Cells
chemical_list: D000950:Antigens, Ly; D060887:B7 Antigens; D014408:Biomarkers, Tumor; C542363:NCR3LG1 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; C527026:Ncr3-ps protein, mouse; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma