Cytomegalovirus vector expressing RAE-1γ induces enhanced anti-tumor capacity of murine CD8+ T cells

Eur J Immunol. 2017 Aug;47(8):1354-1367. doi: 10.1002/eji.201746964. Epub 2017 Jul 4.

Abstract

Designing CD8+ T-cell vaccines, which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show the robust potential of cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8+ T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ, delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1. CMV vector expressing RAE-1γ potentiated expansion of KLRG1+ CD8+ T cells with enhanced effector properties. This vaccination was even more efficient in neonatal mice, resulting in the expansion and long-term maintenance of epitope-specific CD8+ T cells conferring robust resistance against tumor challenge. Our data show that immunomodulation of CD8+ T-cell responses promoted by herpesvirus expressing a ligand for NKG2D receptor can provide a powerful platform for the prevention and treatment of CD8+ T-cell sensitive tumors.

Keywords: CMV vector; KLRG1+ CD8+ T cells; NKG2D; RAE-1γ; Tumor vaccine αPD-1; αTIGIT.

MeSH terms

  • Animals
  • Animals, Newborn
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / immunology*
  • Cytomegalovirus / genetics*
  • Cytomegalovirus / immunology
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Genetic Vectors
  • Humans
  • Immunomodulation
  • Immunotherapy / methods
  • Killer Cells, Natural / immunology
  • Lectins, C-Type
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / prevention & control
  • Neoplasms / therapy
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology

Substances

  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Raet1c protein, mouse
  • Receptors, Immunologic
  • T cell Ig and ITIM domain protein, mouse