Pregnancy and Tumour: The Parallels and Differences in Regulatory T Cells

Abstract

Immunological tolerance plays a critical role during pregnancy as semi-allogeneic fetus must be protected from immune responses during the gestational period. Regulatory T cells (Tregs), a subpopulation of CD4⁺ T cells that express transcription factor Foxp3, are central to the maintenance of immunological tolerance and prevention of autoimmunity. Tregs are also known to accumulate at placenta in uterus during pregnancy, and they confer immunological tolerance at maternal-fetal interface by controlling the immune responses against alloantigens. Thus, uterine Tregs help in maintaining an environment conducive for survival of the fetus during gestation, and low frequency or dysfunction of Tregs is associated with recurrent spontaneous abortions and other pregnancy-related complications such as preeclampsia. Interestingly, there are many parallels in the development of placenta and solid tumours, and the tumour microenvironment is considered to be somewhat similar to that at maternal-fetal interface. Moreover, Tregs play a largely similar role in tumour immunity as they do at placenta- they create a tolerogenic system and suppress the immune responses against the cells within tumour and at maternal-fetal interface. In this review, we discuss the role of Tregs in supporting the proper growth of the embryo during pregnancy. We also highlight the similarities and differences between Tregs at maternal-fetal interface and tumour Tregs, in an attempt to draw a comparison between their roles in these two physiologic and pathologic states.

Keywords: immunological tolerance; immunotherapy; maternal-fetal interface; regulatory T cells (Tregs); tumour.

Figure 1

Origin and mechanisms of Tregs in pregnancy and cancer. (A) After conception, the seminal fluid encounters the uterine tissue. The presentation of paternal antigens by dendritic cells (DCs) to T cells as well as other soluble factors in the seminal fluid favour the induction of regulatory T cells (Tregs). The uterine Tregs express markers such as CTLA-4, PD-1, and Foxp3, and expand locally in the endometrium during early pregnancy (left panel). Uterine Tregs express factors such as IL-10 which inhibits the proliferation and function of T effector cells (Teff); TGF-β which inhibits the function of cytotoxic natural killer (NK) cells; and HO-1 which maintains decidual DCs in an immature state. These immature DCs express higher levels of IL-10 that further supports the immune-suppressive phenotype of uterine Tregs. Tregs also induce the expression of IDO by tolerogenic DCs (tDCs) which inhibits Teff cell function (right panel). (B) Cells in tumour microenvironment release chemokines that recruit Tregs expressing chemokine receptors such as CCR4, CCR5 and CCR8. Tumour Tregs have thymic origin and interact with diverse cell types in the tumour microenvironment (left panel). IL-2 is produced by Teff cells, which is sequestered by Tregs as they constitutively express IL-2 receptor subunit CD25, thus decreasing the bioavailability of IL-2 to Teff cells and inhibiting their function. Tregs may control DCs’ activity through CTLA-4-CD80/86 axis. Tregs also produce immunosuppressive cytokines such as IL-10, TGF-β, and IL-35 that further inhibit the function of Teff cells and antigen-presenting cells (APCs) (right panel). PGE, Prostaglandin E; TGF-β, Transforming growth factor-β; HO-1, Heme oxygenase-1; IDO, Indoleamine 2,3-dioxygenase. Created with BioRender.com.

Figure 2

Parallels and dissimilarities between uterine and tumour Tregs. (A) Uterine Tregs display several tissue adaptations which mimic tumour Tregs. Both uterine and tumour Tregs are characterised by higher expression of BATF and PRDM1. These cells also demonstrate increased suppressive abilities with elevated levels of IL-10 in comparison to their blood counterparts. Uterine and tumour Tregs exhibit an effector phenotype with increased expression of molecules such as TIGIT, PD-1, OX-40, CTLA-4 and CD25. (B) A major difference between uterus and tumour microenvironment is inflammatory milieu of these two tissues. Uterine microenvironment oscillates between T helper type 1 (Th1) and Th2 during pregnancy while tumour growth is fostered by Th2-polarised microenvironment. Uterine Tregs respond to ‘paternal non-self’ and ‘maternal self’ antigens and expand locally. On the contrary, thymus-derived Tregs populate tumour and are exposed to self- and neo-tumour antigens. Uterine and tumour Tregs display phenotypic and functional heterogeneity with uterine Treg subtypes being majorly immune-suppressive while tumour Tregs being both suppressive and non-suppressive. Created with BioRender.com.