Epithelial ovarian cancer is the most common type of ovarian cancer and has a high degree of mortality. Chemotherapy in conjunction with surgery is used to treat ovarian cancers however, there has been a high degree of chemotherapy-resistant tumors leading to a decreased survival rating. Therefore, understanding and overcoming immune tolerance within the tumor microenvironment (TME) is critical for the success of future therapeutics.
A recent study published by Dr. Adaobi Amobi-McCloud et al. in Frontiers in Immunology investigated indoleamine 2,3-dioxygenase (IDO-1) and the kynurenine (KYN) pathway as a potential immunosuppressive target. The study showed that ovarian cancer patients with low IDO-1 expression and high levels of tumor-infiltrating effector T lymphocytes (TIL) had significant increases in their median survival. They examined the roles of IDO-1 in TME immune suppression by exploring the differential expression of IDO-1 between host (IDO-1 KO mice) and tumor (overexpressed IDO-1 ovarian cell line). They found that increased IDO-1 expression in the ovarian cell line, not only alters TRP metabolism, but affects other cellular metabolic pathways. The resulting increase in KYN production facilitated significant upregulation in the cell surface expression of the T-cell inhibitory, PD-1, receptor on host’s CD8+ T-cells. Furthermore, the authors found that KYN-treated CD8+ T-cells had increased chromatin accessibility to other immune-inhibitory receptor genes, Pdcd1 and Lag3. The authors also found AHR binding sites upstream from the PD-1 gene promoter region on CD8+ T-cells, implying a potential crosstalk between IDO-1, AHR, and PD-1. Importantly, this study demonstrates that KYN-mediated PD-1 activity on CD8+ T-cells requires activation of AHR to drive immunosuppression in the TME. Therefore, targeting both IDO-1 and AHR may offer a better immunotherapeutic strategy against ovarian cancer.