CD40 Activation in Vivo Overcomes Peptide-Induced Peripheral Cytotoxic T-lymphocyte Tolerance and Augments Anti-Tumor Vaccine Efficacy

Nat Med. 1999 Jul;5(7):774-9. doi: 10.1038/10495.

Abstract

The outcome of antigen recognition by naive CD8+ cytotoxic T lymphocytes (CTLs) in the periphery is orchestrated by CD4+ T-helper cells, and can either lead to priming or tolerization. The presence of T-helper cells favors the induction of CTL immunity, whereas the absence of T-helper cells can result in CTL tolerance. The action of T helper cells in CTL priming is mediated by CD40-CD40 ligand interactions. We demonstrate here that triggering of CD40 in vivo can considerably enhance the efficacy of peptide-based anti-tumor vaccines. The combination of a tolerogenic peptide vaccine containing a minimal essential CTL epitope with an activating antibody against CD40 converts tolerization into strong CTL priming. Moreover, CD40 ligation can provide an already protective tumor-specific peptide vaccine with the capacity to induce therapeutic CTL immunity in tumor-bearing mice. These findings indicate that the CD40-CD40 ligand pair can act as a 'switch', determining whether naive peripheral CTLs are primed or tolerized, and support the clinical use of CD40-stimulating agents as components of anti-cancer vaccines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenovirus E1A Proteins / immunology*
  • Animals
  • B-Lymphocytes / immunology*
  • CD40 Antigens / genetics
  • CD40 Antigens / physiology*
  • CD40 Ligand
  • Cancer Vaccines*
  • Cell Transformation, Neoplastic
  • Epitopes / immunology
  • Immune Tolerance
  • Lymphocyte Activation
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / prevention & control*
  • Peptide Fragments / immunology
  • Spleen / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Adenovirus E1A Proteins
  • CD40 Antigens
  • Cancer Vaccines
  • Epitopes
  • Membrane Glycoproteins
  • Peptide Fragments
  • CD40 Ligand