Tumor Therapy in Mice via Antigen Targeting to a Novel, DC-restricted C-type Lectin

J Clin Invest. 2008 Jun;118(6):2098-110. doi: 10.1172/JCI34584.

Abstract

The mouse CD8alpha+ DC subset excels at cross-presentation of antigen, which can elicit robust CTL responses. A receptor allowing specific antigen targeting to this subset and its equivalent in humans would therefore be useful for the induction of antitumor CTLs. Here, we have characterized a C-type lectin of the NK cell receptor group that we named DC, NK lectin group receptor-1 (DNGR-1). DNGR-1 was found to be expressed in mice at high levels by CD8+ DCs and at low levels by plasmacytoid DCs but not by other hematopoietic cells. Human DNGR-1 was also restricted in expression to a small subset of blood DCs that bear similarities to mouse CD8alpha+ DCs. The selective expression pattern and observed endocytic activity of DNGR-1 suggested that it could be used for antigen targeting to DCs. Consistent with this notion, antigen epitopes covalently coupled to an antibody specific for mouse DNGR-1 were selectively cross-presented by CD8alpha+ DCs in vivo and, when given with adjuvants, induced potent CTL responses. When the antigens corresponded to tumor-expressed peptides, treatment with the antibody conjugate and adjuvant could prevent development or mediate eradication of B16 melanoma lung pseudometastases. We conclude that DNGR-1 is a novel, highly specific marker of mouse and human DC subsets that can be exploited for CTL cross-priming and tumor therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / chemistry
  • CD8 Antigens / biosynthesis*
  • Dendritic Cells / cytology*
  • Dendritic Cells / immunology
  • Humans
  • Immunotherapy / methods*
  • Lectins / metabolism*
  • Lectins, C-Type
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Melanoma / pathology*
  • Melanoma / therapy*
  • Mice
  • Models, Biological
  • Neoplasm Metastasis
  • Neoplasms / therapy*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Immunologic / physiology
  • Receptors, Mitogen
  • T-Lymphocytes, Cytotoxic / metabolism*

Substances

  • Antigens
  • CD8 Antigens
  • CLEC9a protein, human
  • Clec9a protein, mouse
  • Lectins
  • Lectins, C-Type
  • Receptors, Immunologic
  • Receptors, Mitogen