ACTivating the Immune Response in Ovarian CaNcer

The goal of this multi-center explorative cross-sectional study is to characterize and phenotype the immune state of ovarian cancer (OC) patients compared to controls without cancer, thereby focusing on the hematopoietic organs and the immune cells originating from these organs. This will be executed by assessing the transcriptional, epigenetic, and functional programming of circulating monocytes and myeloid progenitor cells in OC.

It is hypothesized that OC and its progression are heavily influenced by myeloid cells and their progenitors, mainly through defective trained immunity responses. It is hypothesized that OC patients suffer from a suppressive trained immunity phenotype.

Researchers will compare (1) patients with OC who undergo primary debulking surgery and (2) patients with OC who undergo interval debulking surgery to (3) controls as blood and bone marrow donors to see if there are differences between the transcriptional, epigenetic, and functional signature of i) circulating and intra-abdominal monocytes and ii) bone marrow and spleen myeloid progenitor cells.

Participants will get a:

* Vena puncture
* Bone marrow aspiration
* Tumor biopsy (only cases)
* Spleen biopsy (only cases)

Furthermore, peritoneal fluid will be sent for analysis in all patients.

DESCRIPTION OF THE PROBLEM

Ovarian cancer (OC) is one of the most lethal cancers due to late-stage of disease at diagnosis. Standard therapy consists of debulking surgery and chemotherapy. However, despite this aggressive treatment, recurrent disease almost invariably occurs resulting in a five-year survival rate of approximately 30%. Immunotherapy could be a way to increase survival in OC patients. However, a major barrier to a successful deployment of cancer immunotherapy for ovarian cancer patients is the immunosuppressive tumor microenvironment.

RESEARCH DIRECTION

Tumor-related inflammation is one of the hallmarks of cancers in general. Innate immunity specifically is a common denominator that is involved in the pathogenesis of OC. To improve the patient's outcome and identify novel therapeutic targets, one needs a deeper understanding of the tumor-induced changes in the bone marrow myeloid progenitor cells.

HYPOTHESIS

It is hypothesized that OC and its progression are heavily influenced by myeloid cells and their progenitors, mainly through defective trained immunity responses. It is hypothesized that OC patients suffer from a suppressive trained immunity phenotype. In the future, therapeutic targeting of trained immunity could be explored to develop novel immunotherapies for tumors that are refractory to conventional treatment.

OBJECTIVE

To characterize and phenotype the immune state of OC patients compared to controls without cancer, thereby focusing on the hematopoietic organs and the immune cells originating from these organs.

This will be executed by assessing the transcriptional, epigenetic, and functional programming of circulating monocytes and myeloid progenitor cells in OC.

STUDY DESIGN

Investigator-initiated, multi-center explorative cross-sectional study at the Catharina hospital Eindhoven, Radboud University Medical Center and Eindhoven University of Technology.

STUDY POPULATION

The following patients will be included in the study:

* Group 1. Patients with OC who undergo primary debulking surgery (N=30)
* Group 2. Patients with OC who undergo interval debulking surgery (N=30)
* Group 3. Controls as blood and bone marrow donors (N=30)

MAIN STUDY PARAMETERS/ENDPOINTS

Primary endpoints: transcriptional, epigenetic, and functional signature of circulating monocytes and myeloid progenitors. For transcriptional markers, differentially expressed genes between the different groups will be the focus, with a particular emphasis on antigen presentation and processing pathways, inflammatory pathways (e.g., NF-kB), metabolic pathways and enzymes, and pattern-recognition receptor (PRR) signal transduction. For epigenetic markers, the focus will be on three histone marks positively associated with gene expression and trained immunity: H3K4me3, which marks promoters; H3K4me1, which marks distal regulatory elements (enhancers); and H3K27ac, which marks active promoters and enhancers. For functional markers, the focus will be on the degree of trained immunity response in vitro.

Eligibility Criteria:
Inclusion Criteria:

* Subjects should be at least 18 years old and mentally competent;
* Newly diagnosed patients with OC who go for primary debulking surgery or patients with OC who are scheduled for interval debulking;
* Controls: women who undergo surgery for benign gynaecological conditions under general anaesthesia.

Exclusion Criteria:

* Mentally incompetent;
* Pregnant or breastfeeding;
* Known inflammatory of infectious diseases or an immunosuppressive status;
* Using medication interfering with the immune system;
* Severe comorbidities: other active malignancy (except for basal cell carcinoma and other in situ carcinomas);
* Serious psychiatric pathology;
* A self reported alcohol consumption of \>21 units per week.