The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer

Abstract

Regulatory T cells, a subpopulation of suppressive T cells, are potent mediators of self-tolerance and essential for the suppression of triggered immune responses. The immune modulating capacity of these cells play a major role in both transplantation, autoimmune disease, allergy, cancer and pregnancy. During pregnancy, low numbers of regulatory T cells are associated with pregnancy failure and pregnancy complications such as pre-eclampsia. On the other hand, in cancer, low numbers of immunosuppressive T cells are correlated with better prognosis. Hence, maternal immune tolerance toward the fetus during pregnancy and the escape from host immunosurveillance by cancer seem to be based on similar immunological mechanisms being highly dependent on the balance between immune activation and suppression. As regulatory T cells hold a crucial role in several biological processes, they may also be promising subjects for therapeutic use. Especially in the field of cancer, cell therapy and checkpoint inhibitors have demonstrated that immune-based therapies have a very promising potential in treatment of human malignancies. However, these therapies are often accompanied by adverse autoimmune side effects. Therefore, expanding the knowledge to recognize the complexities of immune regulation pathways shared across different immunological scenarios is extremely important in order to improve and develop new strategies for immune-based therapy. The intent of this review is to highlight the functional characteristics of regulatory T cells in the context of mechanisms of immune regulation in pregnancy and cancer, and how manipulation of these mechanisms potentially may improve therapeutic options.

Keywords: HLA class Ib; cancer; immune tolerance; immunotherapy; preeclampsia; pregnancy; regulatory T cells.

Figure 1

Immune mechanisms during pregnancy and cancer development. Although immunomodulation during pregnancy is a physiological process and in cases of cancer a pathophysiological process, there are a number of similarities in cellular and molecular mechanisms at the feto-maternal interface and in the tumor microenvironment. Tumors and fetuses seem to exploit some of the same immunomodulating mechanisms. Formation of the placenta during pregnancy involves invasion of fetal trophoblast cells into the maternal tissue for anchoring and vascular adaptions. In cancer, local invasion into neighboring tissue is essential for manifestation of malignant growth and the first stage in development of secondary tumors or metastases. Furthermore, several immune cells are present both at the feto-maternal interface and in the tumor microenvironment, here with malignant melanoma as an example. There is increasing evidence that regulatory T cells play important roles both in cancer and in reproduction. [Illustration partly inspired by Holtan et al. (5)].

Figure 2

Characteristics of CD4⁺ regulatory T cell subsets. Different subsets of CD4⁺ regulatory T (Treg) cells exist and play a role in the establishment of tolerance in different physiological and pathophysiological settings. Thymic (t)Tregs and HLA-G⁺ Tregs are developed in the thymus in response to self-antigen, whereas induced (i)Tregs, Tr1 cells and Th3 cells are developed in the periphery in response to antigen presentation and cytokines. Natural Treg and iTregs are characterized by CD25 and FoxP3 expression, while HLA-G⁺ Tregs, Tr1, and Th3 cells are CD25⁻FoxP3⁻, although controversies do exist (see the text for details). The thymus-derived Treg cells mediate their effect mainly through cell contact. In contrast, immune suppression by peripheral induced iTreg, Tr1, and Th3 cells are mediated mainly via secretion of the anti-inflammatory cytokines TGF-β and IL-10.

Figure 3

Schematic overview of similarities in Treg function in central tolerance, fetal tolerance, and cancer tolerance. Tolerance play an important role in both fetal and cancer tolerance. Tregs are developed by presentation of antigens of fetal (fAg) or tumor (tAg) origin. Many tumor cells and fetal extravillous trophoblast (EVT) cells have both diminished or no expression of MHC class II and classical MHC class I molecules. Instead, the EVT cells and some cancer cells express HLA class Ib molecules, e.g., the immune modulatory non-classical HLA-G. HLA-G is able to protect fetal and tumor cells from NK cell lysis, as well as according to a few studies to induce Treg formation. Fetal EVTs and tumor cells are also able to contribute to Treg homeostasis by inhibiting effector T cell activation and proliferation through PD-L1/PD-1 and indoleamine-2,3-dioxygenase (IDO) expression. Decidual (d)NK cells further contribute by inhibiting Th17 responses by IFN-γ expression. Fetal EVTs also express cytokines, e.g., IL-10 and TGF-β that induce Treg development. Tregs limit Teff cells and promote their own proliferation and survival through direct engagement with Teff cells, e.g., via PD-L1/PD-1, by the conversion of ATP to Adenosine (Ado) and cytokine secretion.