Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors

Oncotarget. 2015 Mar 10;6(7):4663-76. doi: 10.18632/oncotarget.3081.

Abstract

In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy.

Keywords: TLR7/8 ligand; colorectal cancer; immunotherapy; pancreatic cancer; radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / therapy*
  • Combined Modality Therapy
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / radiation effects
  • Disease Models, Animal
  • Flow Cytometry
  • Humans
  • Imidazoles / pharmacology
  • Immunoenzyme Techniques
  • Immunotherapy
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / radiation effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / therapy*
  • Quinolines / pharmacology
  • Radiation, Ionizing*
  • T-Lymphocytes, Cytotoxic / immunology
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 8 / agonists*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • 3M 001
  • Cytokines
  • Imidazoles
  • Quinolines
  • TLR7 protein, human
  • TLR8 protein, human
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8