For growth, tumors will reshape the microenvironment , causing NK cells to mistakenly think of fetal growth, thereby polarizing to decidual like NK, dNK-like. DNK-like cells that experience this kind of "inversion" should not be regarded as "bad" NK, but are just "confused" about their own role.
Front. Immunol 2022
"inciting" three key inducing factors for NK cells
1, TGF-β
TGFβ is a multifunctional cytokine belonging to the TGF superfamily. The decidual microenvironment is rich in TGFβ, which can convert pNK cells into decidual phenotyped dNK cells in vitro. In cell culture studies, TGFβ-treated pNK cells expressed CD9, CD49a and CD103, while CXCR3 and CXCR4 increased; they produced VEGF and stimulated trophoblast invasion. TGFβ reduces the cytotoxicity of NK cells and helps maintain maternal and fetal tolerance.
is also rich in TGF-β in the cancer microenvironment, mainly focusing on immunosuppressive functions, which helps tumor occurrence. One of the functions is to reverse cytotoxic NK cells into dNK cells that are mainly transplanted.
2, hypoxia conditions
Another similarity between the tumor microenvironment and the decidua-like microenvironment is hypoxia.
Human pNK cells cultured in vitro under hypoxia conditions, combining TGFβ1 and demethylating agent 5-aza-2'-deoxycytidine, reducing NK cytotoxicity, enhancing VEGFA secretion, and gaining the ability to promote trophoblast invasion. . The surface marker of is D56 bright CD16−/low, and Kir, CD9 and CD49a are expressed, as well as chemokine receptors and CD151, CD62L and CD94, which are unique to dNK cells.
This phenotype is "reversible". When it is separated from the decidual-like microenvironment, polarization will be reversed (such as cultured in 21% oxygen environment).
3, Glycodelin
Glycodelin is a glycoprotein , with four subtypes. Glycodelin-a is widely expressed in decidua and amniotic fluid, and is involved in maintaining normal human reproductive activities.
Glycodelin-a inhibits T cell proliferation and induces the transfer of cytokine profile to th2 type. Glycodelin interacts with l-selectin, activates the ERK signaling cascade, produces IL6 in monocytes , and induces a tolerable phenotype in dendritic cells and macrophages .
Glycodelin-a is the regulator of the NK phenotype . It can convert CD56brightCD16−/low NK cells into dNK-like cells , and regulate angiogenesis of endothelial cells through VEGF and trophoblast invasion. Deacetylation and anti-l-selectin blocking antibodies inhibit the biological effects of CD56brightCD16−/lowNK cells, converting them into dNK-like cells.
Glycodelin-a has also been confirmed to be highly expressed in non-small cell lung cancer , endometrial cancer, etc. As an immunosuppressive factor, it induces NK cells to polarize into dNK-like cells and promotes tumor progression. Three types of subpopulation of
NK cells
1, CD56dimCD16+NK cells
CD56dimCD16+NK cells subpopulation of 1CD56dimCD16+NK cells account for about 90%-95% of peripheral blood NK cells, carrying high levels of cell lysed granules (containing perforin and granzyme ), they are CD11b+CD27dim.
This group of NK cells expresses many inhibitory receptors, such as KIRs and CD94-NKG2A complexes. When lysing functions are not required, they inhibit NK activity and maintain a quiescent state.
CD56dimCD16+NK cells encounter cells expressing high levels of activated ligands and low levels of inhibitory ligands (mainly Class I MHC molecules) (such as virus-infected cells and tumor cells), or mediating antibody-dependent cytotoxicity) , exert cytotoxicity. The main NK activation receptors are NKG2D, NCR and DNAM1.
2, CD56blightCD16−/low NK cells
CD56blightCD16−/low NK cells, accounting for about 5% to 10% of peripheral blood NK, and the phenotype is CD11b−CD27+/−. These cells have poor cytotoxicity, and they can produce cytokine (TNFα and GM-CSF).
CD56dimCD16+NK cell subsets are considered mature or "terminal differentiated". In contrast, the subgroup of CD56blightCD16dim is considered immature. CD56brightCD16dim cells are considered to have a high cell secretion ability, giving them immune regulation ability.
3, dNK cells CD56brightCD16−Kir+
dNK cells can be considered as the third NK subtype, with a phenotype of CD56brightCD16−Kir+, and there are two cell markers CD9 and CD49a.
CD9 is a member of the tetraspanin family and is associated with a variety of integrin adhesion receptors that regulate cell migration and invasion. CD9 was upregulated by TGFβ. CD9 is also present in exosomes. CD49a constitutes the α-subunit of the α1β1 integrin receptor (VLA1), which binds to the type IV collagen enriched in the basement membrane. single-cell sequencing of was performed on the early maternal and fetal interface of humans, and three types of dNK cells (dNK1, dNK2 and dNK3) were identified, all expressing CD9 and CD49a.
dNK cells produce a large number of proangiogenic cytokine in vitro, including VEGF, CXCL8 and angiopoietin, as well as a large amount of IFNγ. They are crucial for decidual vascularization and the formation of spiral arteries. In addition, dNK cells secrete matrix metalloproteinases MMP9 and MMP2, destroying the extracellular matrix and participating in vascular remodeling and trophoblast invasion.
dNK cells are crucial in maintaining immune balance, and they are immunosuppressive cells. Various data suggest that dNK cells are key sentinel cells to control local inflammation and maintain maternal and fetal interface tolerance. DNK cells that lose their killer phenotype provide an embryo-compatible microenvironment that supports healthy pregnancy. It is reported that CD56brightCD25+ decidual NK cells transport to the maternal and fetal interface in early pregnancy, and their migration is mediated by CXCR4 and CXCR3, respectively, which are the chemokine receptors of the ligands CXCL12 and CXCL10, respectively.
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Reference
Marc A Schneider et al, Glycodelin: A New Biomarker with Immunomodulatory Functions in Non-Small Cell Lung Cancer, Clin Cancer Res . 2015 Aug 1;21(15):3529-40
Garce´ s -La´ zaro I, Kotzur R, Cerwenka A and Mandelboim O (2022) NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy. Front. Immunol. 13:924775
