Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages

Abstract

The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

Keywords: STAT3; aryl hydrocarbon receptor; c-KIT; dendritic cells; indoleamine 2,3-dioxygenase; macrophages; ovarian cancer; regulatory T cells.

Figure 1

Key signaling pathways that drive immune suppression by tumor-associated macrophages. Major pathways activated via tyrosine kinase receptors or c-KIT/PI3K/Akt signaling (activated by stem cell factor, which is abundantly expressed in ovarian cancer) converge on STAT3 and CREB activation and induction of HIF-1α under hypoxic conditions.

Figure 2

A model of IDO/AhR/wnt/β-catenin circuitry in the ovarian tumor-associated microenvironment. Ovarian tumor expression of wnt7a leads to engagement of LRP5/6 and frizzled receptors on tumor-associated myeloid cells, resulting in release of β-catenin from the axin/APC/GSK3β complex, followed by translocation to the nucleus, association with TCL/LEF and expression of IDO. Expression of wnt7a is negatively regulated by SFRP4. Kynurenine produced by IDO binds myeloid cell AhR, resulting in association of AhR with its nuclear translocator (ARNT) and subsequent transcriptional activation of IDO, ALDH1 and IL-6 expression. ALDH1 contributes to catabolism of retinoid to retinoic acid (RA), and IL-6 drives to a positive feedback loop involving STAT3 activation, IDO expression, kynurenine production and AhR signaling. STAT3 activation also shapes an M2 macrophage phenotype characterized by high IL-10 production. RA binds T cell retinoic acid receptors (RAR/RXR) and induces Foxp3 expression and Treg differentiation. Kynurenine binds T cell AhR, which dissociates from ARA9/HSP90, binds ARNT and induces expression of Foxp3, DNA methyl transferase (DNMT, which demethylates the Foxp3 promoter), IL-10 and the AhR repressor (AHRR), which provides negative feedback for inhibition of AhR signaling.