Chimeric NKG2D T cells require both T cell- and host-derived cytokine secretion and perforin expression to increase tumor antigen presentation and systemic immunity

J Immunol. 2009 Aug 15;183(4):2365-72. doi: 10.4049/jimmunol.0900721. Epub 2009 Jul 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics*
  • Antigen Presentation / immunology
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / metabolism*
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Cells, Cultured
  • Cytokines / metabolism*
  • Epitopes, T-Lymphocyte / administration & dosage
  • Epitopes, T-Lymphocyte / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / immunology
  • Immunity, Innate / genetics
  • Immunotherapy, Adoptive* / methods
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutant Chimeric Proteins / administration & dosage
  • Mutant Chimeric Proteins / genetics*
  • NK Cell Lectin-Like Receptor Subfamily K / administration & dosage
  • NK Cell Lectin-Like Receptor Subfamily K / genetics*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy
  • Perforin / biosynthesis*
  • Perforin / genetics
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / transplantation
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • Antigens, Neoplasm
  • Cytokines
  • Epitopes, T-Lymphocyte
  • Klrk1 protein, mouse
  • Mutant Chimeric Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Perforin