Author:

Abstract:

Ovarian cancer is the second most lethal type of gynecological tumor in women with an incidence rate of 12.5 per 100 000 women. Most patients are diagnosed at an advanced stage, which leads to a poor prognosis. High-grade serous ovarian cancer (HGSOC) is the most frequent histological subtype. Standard therapy consists of debulking surgery in combination with platin-based chemotherapy. As chemo-resistance remains an important issue in relapsed ovarian cancer, research is focusing on novel targeted therapies. Immune escape is an important mechanism for tumor resistance as described in the hallmarks of cancer, which remains poorly explored in ovarian cancer. The presence of immunosuppressive cells is an important contributing factor in immune escape. These cells are present in the tumor microenvironment (TME) due to the secretion of chemokines, cytokines and other mediators produced by the tumor and immune cells present in and around the tumor. These immunosuppressive cells will start producing cytokines that will strengthen the immunosuppressive effects, leading to a downward spiral of effects, all contributing to the escape of tumor cells from the immune surveillance. Currently the most relevant immunosuppressive cells appear to be the regulatory T cells (Treg), the myeloid- derived suppressor cells (MDSC) and the tumor-associated macrophages (TAM). In ovarian cancer, the presence of Treg and TAM in the TME is correlated with poor survival. The goal of immunotherapy is to increase the influx of cytotoxic T cells in this immunosuppressive TME. Although immunotherapy successfully induces an immune response, which leads to T cell infiltration, the effects on tumor control (and therefore survival) are disappointing in ovarian cancer. Therefore, we believe that combinatorialstrategies are needed to overcome immunosuppression, to allow more ovarian cancer patients to benefit from the long-term responses of immunotherapy. For this purpose, it is important to gain insight into the immunological context of ovarian cancer patients, to be able to manipulate the immunosuppressive microenvironment. We optimized the ID8 ovarian cancer mouse model for immunotherapy research. We adapted the existing protocol for the generation of murine DC loaded with immunogenic hyp-PDT tumor lysate. Unfortunately, DC immunotherapy alone did not result in survival benefit. We were able to demonstrate by a retrospective serum study that immunosuppression washighly present in ovarian cancer, which makes it challenging to develop an effective immunotherapeutic strategy.. In addition we were able to correlate immunosuppressive cytokines to CA125, neutrophil-to-lymphocyte ratio and platelet count in blood. In a prospective study, we defined an immune signature (containing ratio's of immune cells in peripheral blood) that could discriminate between benign and malignant ovarian tumors. Furthermore, we also investigated the changes in immune cells during first-line treatment of ovarian cancer. In the mouse model, we observed that the adaptive immune system was unable to control tumor growth, most likely because it is overwhelmed by innate immunosuppression. We identified a key role for mMDSC in tumor progression and immunosuppression in the mouse model. Both our human and murine data point towards an important role for the mMDSC, whereas until now the knowledge of ovarian cancer immunobiology was limited to the behavior of the adaptive immune system in the primary tumor. In summary, we believe that the answer for ovarian cancer immunotherapy lies in a fine-tuned approach combining immunotherapy with a compound to reduce the immunosuppressive function of MDSC. Our results have given a first insight in this complex landscape and will be the basis for future experiments.