RESEARCH

Ovarian cancer, with high grade serous adenocarcinoma as the most common tumor subtype, ranks fifth as the cause of death from cancer in women. Although most cancers are highly sensitive to first-line adjuvant chemotherapy, the disease has an overall 5-year survival rate of less than 40%. Several features characteristic of ovarian HGSC contribute to its fatal nature, including the shedding of tumor cells at a very early stage of the disease, their spreading to other pelvic and peritoneal organs via the peritoneal fluid to form transcoelomic metastases and the tumor-promoting and immune suppressive effect of the peritoneal tumor environment, frequently formed by the malignancy-associated ascites building up in the peritoneal cavity.

Chemotherapy failure can result from inherent or acquired resistance, the latter eventually developing in most patients after repeated therapy cycles. However, at the time of first relapse, tumor cells frequently still display a similar chemosensitivity as the primary disease. This possibly results from a state of transient chemoresistance caused by cells escaping chemotherapy-induced cell death by entering a non-cycling state with low metabolic activity. This is a characteristic feature of detached tumor cells and spheroids in the peritoneal fluid or ascites, which may thus provide a protective niche. Another major determinant of therapy success is the patient’s immune response as shown by the association of with a longer survival with cytotoxic T lymphocyte (CTL) infiltration and the efficacy of anti-PD1 antibodies in a subgroup of ovarian cancer patients. These observations clearly suggest that a cure of ovarian HGSC may be best achievable by combining chemotherapy or tumor cell targeted drugs with the re-activation of an anti-tumor immune response by CTL, natural killer (NK) cells and tumor-associated macrophages (TAMs). It is a central goal of OvaRA to contribute to these aims

TAMs play a pivotal role at different stages by promoting adherence, invasion and growth. On the other hand, tumor cells inhibit TAMs and block the cytotoxic activity of CD8+ cells, thereby contributing to the inefficiency or failure of immune therapy. Based on this model we investigate how tumor cell-autonomous genetic mechanisms and the micromilieu established by the major cell types in the ovarian HGSC microenvironment cooperate to establish transient resistance to chemotherapy and impair immune surveillance. We focus on the chemoresistance of detached tumor cells, their invasion into serous membranes, the pro-tumorigenic and immune suppressive conversion of TAMs and the inhibition of CTLs and NK cells, the latter as downstream effectors of macrophages. We anticipate that elucidating the mechanisms underlying these processes offers opportunities for the development of novel therapeutic intervention strategies. We strongly

feel that these aspects can be analyzed in a clinically meaningful way best with patient-derived material, and we therefore pursue this approach as a central strategy of our research. 

OvaRA, University of Marburg, Germany

© 2017 by Rolf Müller