PhD ceremony Ms. M.J.M. Gooden: Immunologic aspects of ovarian cancer
|When:||Mo 10-06-2013 at 16:15|
PhD ceremony: Ms. M.J.M. Gooden, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen
Dissertation: Immunologic aspects of ovarian cancer
Promotor(s): prof. H.W. Nijman, prof. C.A.H.H. Daemen
Faculty: Medical Sciences
Ovarian cancer is the most lethal gynecologic malignancy, because it is usually diagnosed at a late stage and current treatment (surgery and chemotherapy) is often not successful in eradicating the disease altogether. Thus, it is important to find new treatment options. In this context, attacking the tumor via the patient’s own immune system is a promising strategy. Immune cells are capable of recognizing cancer cells, because cancer cells differ from healthy cells. In this process of recognition and destruction of cancer cells, T-lymphocytes play a key role.
The objective of this thesis is to characterize the immune response against ovarian cancer cells. First, we determined which T-lymphocyte subsets are present in ovarian cancer. We found that the presence of cytotoxic T-lymphocytes, which are capable of destroying cancer cells directly, is predictive of a better prognosis. Moreover, a high ratio between these cytotoxic T-lymphocytes and immunosuppressive regulatory T lymphocytes is an even stronger predictor. However, the tumor has several mechanisms to counteract the immune response. We investigated components of the antigen processing and presentation pathway, which is key in recognition of tumor cells by immune cells. Also, we determined HLA-E expression, which can inhibit cytotoxic T-lymphocytes via a specific receptor which is not normally present on these T-lymphocytes. We indeed found that an intact antigen processing and presentation apparatus and a lack of HLA-E expression predicted the success of the anti-tumor immune response. Next, we investigated the role of chemokine CXCL16. The soluble form, sCXCL16, can be measured in blood. Surprisingly, it was not predictive of lymphocyte invasion in the tumor, but instead strongly predicted shorter survival. Further in vitro studies revealed that the presence of sCXCL16 was a reflection of the activity of certain protein cleaving enzymes, i.e. ADAMs. These enzymes are necessary for release of sCXCL16 in the blood stream, but also play a key role in tumor metastasis. Since ADAM activity is difficult to quantify in patients, sCXCL16 is a suitable pseudo-marker. Finally, we investigated a potentially T-lymphocyte activating glycoprotein, Galectin-9, which can be found in ascites (abdominal fluid) of ovarian cancer patients. It is thought to destroy T-lymphocytes, but we showed that in low doses, it is actually a potent activator of T-lymphocytes. Further studies are performed to determine whether Galectin-9 is indeed of potential use in (ovarian) cancer treatment.