The Role of reactive oxygen species in cytotoxic immunity against cancer.

What are the roles of reactive oxygen species (ROS) in the cytotoxic immunity against cancer and how can they be targeted to eradicate cancer?

Reactive Oxygen Species (ROS), Cytotoxic Immunity and Cancer.

The role of the immune system in the fight against cancer is undeniable. In this regard, Natural killer (NK) cells and cytotoxic T lymphocytes (CTL) are respectively innate and adaptive cytotoxic lymphocytes dedicated to kill cancer cells. In the lab, we are using a model of glioblastoma multiforme (GBM), a very lethal primary brain tumor, to investigate the cell death mechanism triggered by these cytotoxic lymphocytes and how they are regulated by microenvironmental metabolites such as reactive oxygen species (ROS) in order to design new therapeutics. To meet this goal, we use combined approaches at the intersection of biochemistry, chemistry, cell biology, proteomics, genomics and bioinformatics.

  • I committed all my effort to beat cancer.

The role of the immune system against cancer was demonstrated as primary and acquired immunodeficiency is associated with increased susceptibility to cancer. Furthermore, the size of the immune infiltrate in primary tumor is a good prognosis for patient survival, explaining why blockage of immune checkpoint receptors is a very promising immunotherapy strategy. However, the occurrence of cancers and the resistance to blockage of these immune checkpoint receptors are the direct demonstration that tumor cells are capable of evading the host immune surveillance, and this ability to escape immune recognition and elimination, essential for cancer development, is now considered as a new feature in the hallmark of cancer. This is also true for glioblastoma multiforme, a very aggressive primary brain tumor, the cancer model under investigation in the lab. The natural killer (NK) cells and cytotoxic T lymphocytes (CTL) are the cytotoxic lymphocytes dedicated to engage and kill the cancer cells. A better understanding of factors regulating the dynamics of interaction between cancer cells and these cytotoxic lymphocytes is necessary to develop new therapeutics harnessing the patient own immune system to beat the disease.

 In the lab, we focus on the role of immune inhibitory metabolites such as reactive oxygen species (ROS). ROS are pleotropic factors resulting from the cancer cell metabolic shift and the hypoxic microenvironment and they are strong candidates capable of orchestrating the reprogramming of the tumor microenvironment for tumor progression. Supporting this hypothesis, H2O2 modulates genes expression following the activation of redox responsive transcription factors. In addition, some of our preliminary data suggest that the cancer cell redox state could regulate lymphocyte function. Interestingly, we have also found that cancer cells, under the attack of the cytotoxic lymphocytes, experienced a massive ROS production that is necessary for their demise. Taken together ROS play a complex role in the dynamics of cancer-immune cell interaction. The Martinvalet’ lab investigates the role of the ROS in the cytotoxic immunity against glioblastoma multiforme both from the standpoint of the target cancer cells and the cytotoxic lymphocytes.

  

Denis Martinvalet

  • 2000-2001: Research Fellow, Manitoba Institute of Cell Biology, Winnipeg, CA.
  • 2001-2006: Research Fellow, Immune Disease Institute, Harvard Medical School, Boston, USA.
  • 2006-2009: Instructor, Immune Disease Institute, Harvard Medical School, Boston, USA.
  • 2009-2016: Group Leader, Dept. Cell Physiology and Metabolism, University of Geneva, CH.
  • 2018-   Assistant Professor, Dept. of Biomedical Sciences, University of Padua, IT.

Selected Awards

  • 2016 – Member of the European Academy of Tumor Immunology
  • 2015 – Member of the American Association for the advancement of science.
  • 2007-2009 – Board of Directors, Sickle Cell Disease Association of America, Boston Chapter.