Lessons from Immune Escape Mechanisms of Embryo Development in Uterus

Lessons from Immune Escape Mechanisms of Embryo Development in Uterus

WU,Tianfang,CHENG,Gong

Gynecological Hospital Affiliated to Beijing Medical University,Beijing 100000,China

The development of semi-allogenic embryo in uterus during pregnancy is an immunological paradox,the im-mune tolerance in the fetomaternal interface is naturally established to prevent the embryo rejection.Solid tumors exist as a“new life”develop years,employ local or dis-tant body nutrients to adapt,grow and metastasize to different organs of host.The development of embryo and tumor shares numerous similarities across the immune landscape and microenvironmental factors.Lessons from embryo development can increase our understanding on tumorigenesis and its components that could potentially transform anticancer therapeutic interventions.

Embryo implantation is occurring in a precisely con-trolled“window”period.In response to implanting em-bryo,the surrounding endometrium undergoes cellular transformation,a process known as decidualization,to ac-commodate embryonic growth and invasion[1].The uterus decidua as well as the upcoming developed placenta are physical barriers between the mother and the fetus,play key roles in promoting the anti-inflammatory environment necessary for embryo development and pregnancy pro-gression.

Distinct factors,including genetical,biological and immunological,work corporately in guiding fetus preven-tion during pregnancy[2].Here we mainly illustrate major mechanisms of allogenic embryo escape the mother’s im-mune systems.

Lack of expression of classic HLA-I molecules

Healthy placental trophoblast cells are lack of paternal MHC class II or Ia molecules,which normally present antigens to the cytotoxic T lymphocytes.However,class Ib non-polymorphic molecules,such as HLA-G,HLA-E and HLA-F,are highly expressed on tropoblasts,and play roles in inhibiting the proliferation and cytotoxic of T lymphocytes and NK cells[3].This point was believed to be one explanation of why embryo escape the immu-nosurveillance of the mother.However,this view has been questioned recently since the rate of pregnancy was not af-fected by transgenic expression of parental MHC molecules in several studies,suggesting that the lack of MHC class is dispensable in maintaining the fetomaternal tolerance[4].

Activation of a type Th2 regulatory lymphocyte

response

The T helper type 1(Th1)-Th2 theory defines that Th1 cells-derived cytokines,such as IFN-γ,predominantly promote cell-mediated immunity,whereas cytokines pro-duced by Th2 cells,such as IL-4,induce humoral immu-nity and the production of immunoglobulin antibodies.Pregnancy was proposed as a Th2 phenomenon,and a shift from Th1 to Th2 is essential for a successful preg-nancy.However,this Th1-Th2 paradigm has been chal-lenged since IFN-γthat is detrimental to human pregnancy facilitates uterine vascular modification,decidualization and uNK cells differentiation in mice[5].With the evidenc-es of more subtypes on differentiation of CD4+T helper cells,The Th1/Th2/Th17 and regulatory T cells(Tregs)paradigm during pregnancy has been proposed and drawn extensive attention of immunologists[6].

Production of immunosuppressive cytokines

The uterus could produce multiple cytokines,such as IL-4,IL-10,IL-5,PGE2 and M-CSF,to induce Th2 re-sponse for successfully pregnancy.On another hand,T cell attracting chemokines in decidua were epigenetically silenced,which lead to the effector T cells fail to infiltrate into the decidua in response to fetal challenge[7].Besides,DC cells were entrapped by decidua and thus minimizing the activation of naïve T cells that responsible for fetal rejection during early pregnancy at the fetomaternal inter-face[8].NK cells in placenta present different CD56+cells secreting IL-8 and IL-6 to reduce vascular resistance[9].It has been reported that the number of NKs significantly reduced in pregnancy and their capability to produce IFNγis also dampened.Placental Tregs modulate active T cells using a series of repressive reactions including expropri-ation of IL-2 as well as increased release cytokines and other molecules[10].

In general,precise modulations of immune system maintain successful pregnancy till parturition,while un-controlled immune suppression preserves the tumor for an indefinite period.A comprehensive study of immunoreg-ulatory mechanisms of embryo development during preg-nancy could provide fresh ideas on how to overcome tu-mor immune evasion and inspire more durable approaches to arrest cancer progression.

References

[1]Zhang,S.,Lin,H.,Kong,S.,Wang,S.,Wang,H.,Wang,H.,Armant,D.R.,2013.Physiological and molecular determinants of embryo implantation.Mol Aspects Med.34,939-980.

[2]Macintyre,G.,Goranova,T.E.,De Silva,D.,Ennis,D.,Piskorz,A.M.,Eldridge,M.,Sie,D.,Lewsley,L.A.,Hanif,A.,Wilson,C.,et al.,2018.Copy num-ber signatures and mutational processes in ovarian carcinoma.Nat Genet.50,1262-1270.

[3]Ridolfi,L.,Petrini,M.,Fiammenghi,L.,Riccobon,

A.,Ridolfi,R.,2009.Human embryo immune escape mechanisms rediscovered by the tumor.Immunobiol-ogy.214,61-76.

[4]Ander,S.E.,Diamond,M.S.,Coyne,C.B.,2019.Immune responses at the maternal-fetal interface.SciImmunol.4.

[5]Ashkar,A.A.,Di Santo,J.P.,Croy,B.A.,2000.In-terferon gamma contributes to initiation of uterine vascular modification,decidual integrity,and uterine natural killer cell maturation during normal murine pregnancy.J Exp Med.192,259-270.

[6]Saito,S.,Nakashima,A.,Shima,T.,Ito,M.,2010.Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy.Am J Reprod Immunol.63,601-610.

[7]Nancy,P.,Tagliani,E.,Tay,C.S.,Asp,P.,Levy,D.E.,Erlebacher,A.,2012.Chemokine gene silencing in decidual stromal cells limits T cell access to the ma-ternal-fetal interface.Science.336,1317-1321.

[8]Collins,M.K.,Tay,C.S.,Erlebacher,A.,2009.Den-dritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice.J Clin Invest.119,2062-2073.

[9]James-Allan,L.B.,Buckley,R.J.,Whitley,G.S.,Cartwright,J.E.,2020.The phenotype of decidual CD56+lymphocytes is influenced by secreted factors from decidual stromal cells but not macrophages in the first trimester of pregnancy.J Reprod Immunol.138,103082.

[10]Robertson,S.A.,Care,A.S.,Moldenhauer,L.M.,2018.Regulatory T cells in embryo implantation and the immune response to pregnancy.J Clin Invest.128,4224-4235.