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Antitumoral Effects of Lipid A: Preclinical and Clinical Studies
  1. Alena Pance,
  2. Danièle Reisser,
  3. Jean-François Jeannin
  1. From the Cancer Immunotherapy Research Laboratory, Faculty of Medicine, Ecole Pratique des Hautes Etudes, Dijon, France.
  1. Address correspondence to: Dr. D. Reisser, Cancer Immunotherapy Research Laboratory, Faculty of Medicine, Ecole Pratique des Hautes Etudes, INSERM U517, 7 Boulevard Jeanne d/Arc, F-21079 Dijon, France. Email: reisserd{at}u-bourgogne.fr

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INTRODUCTION

Cancer is the second cause of death in developed countries. Surgery and radiotherapy are widely used in the treatment of localized and attainable tumors. Chemotherapy and immunotherapy are used as adjuvant treatments or as therapies for advanced-stage diseases. However, chemotherapy often leads to a high relapse rate because of drug resistance, which might be overcome by immunotherapy. When the immune system is not destroyed by chemotherapy, it is able to recognize tumor-specific antigens and eventually can eliminate the cancer cells.

One of the means of achieving this goal is the use of lipopolysaccharides (LPSs). LPSs are components of the outer membrane of Gram-negative bacteria and are composed of a polysaccharide, an oligosaccharide core, and lipid A. These compounds have the property of inducing the secretion of various cytokines, such as tumor necrosis factor-α (TNF-α),1interferon-γ (IFN-γ),2interleukin 1-β (IL1-β),3and interleukin-6 (IL-6),4as well as activating immune cells, including neutrophils,5macrophages,6and CD4 and CD8 T lymphocytes that infiltrate the tumors.7,8Furthermore, these compounds have been shown to decrease suppressive cytokines such as transforming growth factor-β (TGF-β).4,9

The first assays with bacterial extracts containing LPS to be used as a treatment for cancer were performed in clinical trials in 1898.10A half-century later, the antitumoral effect was attributed to LPSs in murine subcutaneous tumors,11and eventually it was demonstrated that this effect is due to the lipid A component of LPSs.12Because lipid A and its derivatives are less toxic than LPSs, most anticancer treatments aimed at activating an immune response against tumors have been developed with the use of natural lipid A or synthetic analogs, either alone or as adjuvants, to enhance the efficacy of therapeutic anticancer vaccines.

Animal models permit the investigation of the mechanisms of the …

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