My research concerns the mechanisms that control the immune response: this remarkable machinery is able to adaptively detect and eliminate threats ranging from viruses and bacteria to parasitic infections, to even malfunctioning cells of the body itself. Cancer touches on many aspects of immune recognition, which we study to define mechanisms that may be pursued for immunotherapeutic use. Our studies aim to improve the expression of peptide/MHC class I (MHC-I) complexes on dendritic cells (DC) and on the tumor cell surface, for enabling cytotoxic T lymphocytes (CTL) to exert their unique immunological function to kill tumor cells.
My team has helped define essential requirements for the recognition and activation of CTL responses. We showed that antigen targeting to specific uptake receptors on human DC enhances their ability to activate and expand CTL responses. We discovered that contact with CD4 T-cells ‘licenses’ DC, facilitating them to activate CTLs by enhancing the peptide/MHC-I transport to the DC surface, by improving the development of antigen-specific CTLs in cancer patients receiving stem cell transplantation treatment, and by improving antigen-specific T-cell responses by stimulating the release of DC-derived extracellular vesicles.
We were the first to describe how dysfunction of the mitochondrial energy metabolism links to the production of the immune stimulatory cytokine IL-1b, by study of a rare metabolic immunodeficiency disease. My team contributed original new insights how peptide/MHC-I expression can be improved on neuroblastoma tumors, as a means to improve tumor-specific CTL responses.
Neoantigens for lymphoma immunotherapy
Non-Hodgkin’s Lymphoma is a cancer that starts when a certain type of white blood cell, lymphocytes, starts to share uncontrollably. In 2015, more than 1800 people in the Netherlands were diagnosed with aggressive non-Hodgkin’s lymphoma; the average survival is now around 62%. In recent years, so-called antigen-specific immunotherapy has proven successful for different types of cancer, but for non-Hodgkin lymphoma, successful immunotherapy has not yet been established. The reason for this is that for non-Hodgkin’s lymphoma, few leads or antigens have been described for immunotherapy. In this project we aim to test unique differences between healthy cells and B-cell lymphoma cells as a starting point for cancer immunotherapy.
Based on our preliminary work, we expect that these targets can be found in lymphoma and not in healthy cells, and that they can be useful for immunotherapy. To apply the results from this project, we have already contacted a company with which we are already collaborating for the development of cancer immunotherapy. We therefore think that the application of results in patient care, assuming that everything runs smoothly, will proceed without delay.