Exosome-mediated immunosuppressive mechanisms and their role in pregnancy and epithelial ovarian cancer

In a collaborative translational clinical and basic research project we study:

1. normal pregnancy and related disorders such as pre-eclampsia, and
2. high-grade serous carcinoma of the ovary (HGSC) and severe endometriosis that can impair fertility and booster the risk for HGSC.

We investigate how patients’ immune system is modulated with a special focus on exosomes, secreted by cancer, placenta and endometroid tissues. These exosomes are immunosuppressive and use a variety of molecular mechanisms to blunt host immunity and escape immune attack. This is beneficial for the fetal survival and development but detrimental for cancer- and endometriosis patients.

By comparison of cytokines and similar exosome types from a physiological condition (pregnancy) to pathological conditions as pre-eclampsia, endometriosis and HGSC we define cancer-specific immune mechanisms and molecular patterns. We ask the questions: “How is immune suppression created and controlled in pregnancy, pregnancy disorders and cancer?”  “How are exosomes involved in this process”?

Immunosuppressive mechanisms work in concert

Our studies show that several immunosuppressive mechanisms work in concert to create immune tolerance in pregnancy and cancer. Our cytokine analyses reveal that the cytokine mRNA profiles in normal pregnancy, endometriosis and cancer suppress cytotoxicity by inadequate IFN gamma production and promote T-regulatory responses by enhanced production of TGF beta and IL-10. Especially interesting is the local T regulatory cell production in the endometriotic tissue explaining why this tissue survives in ectopic intraperitoneal locations and causes a chronic disease.

In contrast, vigorous inflammation and enhanced NK-cell cytotoxicity prevail in pre-eclampsia and cause placenta damage that leads to abortions and/or premature birth, commonly observed in this disease. Exosomes, produced by trophoblast-, epithelial endometrial- and ovarian cancer cells contribute and finely tune these immunosuppressive processes at the molecular level by

• specific downregulation of the major cytotoxic immune surveillance receptor NKG2D,
• induction of apoptosis of activated lymphocytes through FasL and TRAIL, and
• exhaustion of activated effector cells and promotion of T regulatory cells via PD-1/PD1-L.

Our recent studies, in the pipeline of publication, describe in details PD-1L expression and distribution in human placenta and provide evidence that propose a new pathogenetic mechanism in endometriosis.

As a result of our studies we have defined and suggested immunosuppressive signatures that classify exosomes functionally and can be used as tools in clinical settings for diagnostic and therapeutic purposes (Mincheva-Nilsson L, 2021, Front. Immunol. 12:717884).