title: Chimeric NKG2D T cells require both T cell- and host-derived cytokine secretion and perforin expression to increase tumor antigen presentation and systemic immunity.
abstract: Treatment of mice bearing established ovarian tumors with T cells expressing chimeric NKG2D receptors (chNKG2D) develop protective host immune responses to tumor Ags. In this study, the mechanisms that chNKG2D T cells require to induce host immunity against ovarian tumors and which of the host immune cells are involved in tumor elimination were determined. Treatment with chNKG2D T cells led to a sustained, increased IFN-gamma production by host NK, CD4(+), and CD8(+) T cells in the spleen and at the tumor site and this continued for many weeks after T cell injection. Tumor Ag presentation was enhanced in chNKG2D T cell-treated mice, and there were greater numbers of tumor-specific T cells at the tumor site and in draining lymph nodes after treatment with chNKG2D T cells. The increase in host cell cytokine secretion and Ag presentation was dependent on chNKG2D T cell-derived perforin, IFN-gamma, and GM-CSF. Host immune mechanisms were involved in tumor elimination because inhibition of tumor growth was limited in mice that lacked perforin, IFN-gamma, NK cells, or T and B cells (Rag1(-/-)). There was no role for host-derived GM-CSF or CD1-dependent NKT cells, because mice deficient in these were able to clear tumors as well as treated wild-type B6 mice. In summary, chNKG2D T cells required both cytotoxicity and cytokine secretion as well as the participation of host immune cells for development of a host antitumor immune response and complete efficacy.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Amorette
authors.initials: A
authors.lastname: Barber
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050506:Mutant Chimeric Proteins / Q000008:administration & dosage / Q000235:genetics*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000008:administration & dosage / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D054353:Perforin / Q000096:biosynthesis* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; C527086:Klrk1 protein, mouse; D050506:Mutant Chimeric Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054353:Perforin