Research ArticleExperimental Studies
Open Access

Phenotypic Alteration and Suppression of Cytotoxicity of Decidual NK Cells After Co-culturing With Different Trophoblastic Cell Lines

KORNÉL F. LAKATOS, KEVIN M. ELIAS, KATHLEEN HASSELBLATT, GYÖRGY L. VÉGH, THOMAS MCELRATH, ROSS S. BERKOWITZ and VILMOS FÜLÖP
Anticancer Research November 2025, 45 (11) 4717-4727; DOI: https://doi.org/10.21873/anticanres.17821

Abstract

Background/Aim: Successful conception and pregnancy require a complex and organized communication between the embryo (allograft) and the mother’s (host) immune system. The decidual NK cells (dNK), among other leukocyte subsets, have an important role in orchestrating this immune environment. This study aimed to investigate how exposure to benign and malignant trophoblastic cell lines affects the phenotype and cytotoxic function of dNK cells.

Materials and Methods: In our study, we isolated dNK cells from term, healthy human placentas and sorted them to achieve a pure, CD56 bright, CD16 negative population. These NK cells were co-cultured with HTR-8 (benign) and Jeg-3 (malignant) trophoblastic cell lines for one and five days. The NK cells were isolated again after the exposure to the trophoblastic cells, and their phenotype was assessed again. Their cytotoxicity was also measured and compared to the cytotoxicity of dNK cells not exposed to trophoblastic cells.

Results: After one day of co-culture, dNK phenotype remained unchanged with both cell lines. However, a five-day exposure to Jeg-3 cells resulted in a shift toward a CD56 diminished CD16+ phenotype, resembling peripheral NK cells. Additionally, cytotoxic activity of dNK cells was significantly reduced after co-culture with both cell lines, with a more pronounced suppression observed following exposure to Jeg-3 cells.

Conclusion: There are certain similarities between the immune evasion of tumor cells and the physiological invasion of the trophoblastic cells of embryonic origin into the maternal decidua. Understanding the ways of interaction between dNK cells and the trophoblastic cells may reveal similar immunological interactions between the host’s NK cells and tumor cells.

Keywords:

Introduction

The fetal-maternal interface has been the focus of intense reproductive immunological and oncological investigation for several decades due to its unique microenvironment. During the pregnancies of eutherian (placental) mammals, the fetus represents a semi-allograft, as half of its genes are paternal. Trophoblastic cells are the first cells to differentiate from the blastocyst during the embryogenesis. They are in direct contact with the maternal immune system and due to their special antigen profile, they are tolerated by the maternal immune system (1, 2). Trophoblastic cells form an outer layer around the growing embryo providing it with nutrients. The trophoblastic cells originate from the fertilized egg, and alongside with the embryonal ectoderm, they form the trophectoderm. As the pregnancy progresses, the trophoblastic tissue proliferates and differentiates creating the placenta. This process is important to create the optimal environment for receiving the blastocyst. By the end of this sequence, a semi allograft (embryo), with a different antigen phenotype is able to invade and penetrate the host’s (mother) tissue. At the frontier of the maternal- fetal barrier, the syncytiotrophoblast is formed (3, 4).

Human uterine NK cells [uNK cells or decidual NK (dNK) cells] are a distinct immune cell subset that plays a key role in normal placentation. While dNK cells and peripheral NK cells are CD3− CD15−, and CD14−, most of the dNK cells are CD16− and CD56 bright. This dNK phenotype is related to diminished cytotoxicity, unlike most peripheral NK cells, which are CD16+ and CD56 diminished and highly cytotoxic (5). Another difference is that the dNK cells express killer cell immunoglobulin- like receptors (KIRs) at a higher level compared to the peripheral NK cells and they express vascular endothelial growth factor (VEGF), placental growth factor (PGF), angiotensin II (ANG2) and transforming growth factor beta 1 (TGFβ1) (6). The proportion of dNK cells among other leukocytes in early pregnancy is extremely high, accounting 70% of all white blood cells (7, 8). This high percentage persists until the 20th week and then it starts to decline until it reaches 10- 35% around the end of pregnancy (9). The high number of dNK cells in the decidua during implantation and throughout early pregnancy and their angiogenic cytokine expression also suggest the importance of dNK cells in decidual angiogenesis. As the extravillous trophoblastic (eVT) cells migrate in the decidua they penetrate under the effect of different immune cells and cytokines of the host. eVT cells express a spectrum of special major histocompatibility complex (MHC)-I molecules including human leukocyte antigens (HLA)-G, HLA-E and HLA-C. In contrast to other cells, they do not express the classic HLA-A and HLA-B antigens. Most of the dNK cell receptors recognize the HLA-G antigen as a ligand preventing its killing function. Cytokines produced by dNK cells, such as interferon (IFN)-γ gamma, tumor necrosis factor (TNF)-α, granulocyte macrophage colony stimulating factor (GCSF), IL-10 (Interleukin 10), and IL-8 (Interleukin 8) may regulate trophoblast invasion (10, 11).

Many of these same processes of placental formation are recapitulated in placental neoplasms. Gestational trophoblastic disease (GTD) covers a wide variety of trophoblastic pathologies including gestational trophoblastic neoplasia (GTN). They are extremely rare but can appear during or after pregnancy. GTN includes invasive hydatidiform mole, placental -site trophoblastic tumor (PSTT), epithelioid trophoblastic tumor (ETT) and choriocarcinoma (12). PSTT is originated from interstitial trophoblasts, while hydatidiform moles and choriocarcinoma arise from villous trophoblasts (13). The ways in which GTN tumors avoid the maternal immune system probably show similarities to those that healthy trophoblastic cells use. The immune suppressive effect of trophoblastic cells on peripheral NK cells in vitro have been demonstrated, but how malignant and benign trophoblasts interact specifically with dNK cells is not known (14, 15). In this study, we isolated dNK cells from fresh, end term placenta and co-cultured them with different trophoblastic cell lines for 1 and 5 days. The trophoblastic cell lines HTR-8 (benign trophoblasts) and Jeg-3 (choriocarcinoma) to explore possible differences in dNK-trophoblast interactions between benign and malignant contexts.

Materials and Methods

IRB Approval. This study was approved by Partners Healthcare Institutional Review Board protocol 2016P001505. According to an institutional discarded tissue protocol, the requirement for written informed consent was waived.

Sample collection and cell lines used. Prospective study participants were selected by review of the operating room schedule for planned singleton cesarean deliveries occurring at term for either breech presentation or elective repeat delivery. Only uneventful gestations were selected. Cases with gestational conditions like gestational diabetes mellitus or preeclampsia were excluded, as well as any cases where placental pathologic evaluation was requested by the obstetrician. The placenta was processed following our protocol to obtain high number of living dNK cells for the co-culturing (16). Briefly, placental tissue was manually morcellated and then digested with collagenase into a single cell suspension, followed by flow cytometry sorting. HTR-8 cells are derived from human, first-trimester invasive eVT cells transfected with the gene encoding for simian virus 40 large T antigen, whereas the Jeg-3 cells are choriocarcinoma cells derived from the Woods strain of the Erwin- Turner tumor by Kohler and associates (17, 18). Both cell lines were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA).

Co-culturing. After isolation from the placenta, dNK cells were kept in NK media (Miltenyi Biotec, NK MACS® Medium, Bergisch Gladbach, Germany) overnight at 37°C, 5% CO2. Both HTR-8 and Jeg-3 cells were seeded on a 6 well plate (30,000 cell/cm3 density) in RPMI+20% FBS medium (Roswell Park Memorial Institute, Fetal Bovine Serum, RPMI-1640, 30-2001™, ATCC, FBS ATCC), 37C°, 5% CO2 for 24 h before the co-culturing. dNK cells were transferred into RPMI medium and added to the already adherent trophoblastic cells to achieve a 1:10 ratio of trophoblastic cells to dNK cells (Figure 1). Controls included dNK cells with no exposure to trophoblastic cell lines or exposure to a different tumor cell type (ovarian adenocarcinoma cell line OVCAR-3, also from ATCC). dNK cells were also kept in RPMI complete media for 5 days but no changes in phenotype or cytotoxicity were detected. Low dose of IL-2 was added (500 IU IL-2/1 ml media, human interleukin-2, Sigma Aldrich, St. Louis, MO, USA) to the plates (samples and controls) at the starting of the co-culturing and on day 3 to achieve dNK cell survival. For each round of experiments, three technical replicates with the same set up were examined simultaneously. The dNK cells were selected from the same, randomly selected placental sample. The experiment was repeated three times using three different placentas.

Figure 1.
Figure 1.

Microphotograph of the dNK cells and HTR-8 co-culture plate. A) Image of HTR-8 cells and dNK cells. The bigger, adherent cells with tentacles are the HTR-8 cells, the smaller cells, sometimes forming clusters, are the dNK cells. B) Image of Jeg-3 cells and dNK cells. Jeg-3 cells form a dense layer, and the adherent clusters are formed of dNK cells.

dNK isolation and cytotoxicity assay. On day 1 and day 5 both the trophoblastic and dNK cells were collected from the plates and dNKs were processed for flow cytometry. The cell sorting was performed using Agilent Cross Laboratory (Santa Clara, CA, USA) software on a BD FACS Aria cell sorter (Franklin Lakes, NJ, USA). The gating strategy to separate the dNK cells from the trophoblastic cells is illustrated in Figure 2. CD3, CD14, CD15, CD16, CD56, DAPI (4′,6-diamidino-2-phenylindole, Sigma Aldrich) staining were applied to analyze NK cell phenotype. Cytotoxicity assays were performed in 96 well U bottom plates using the isolated dNK cells as effector and K 562 cells (ATCC) as target at 5 to 1 and 2.5 to 1 effector to target ratios. dNK cells and target cells were incubated for 4 hours in the dark at 37°C, 5% CO2. The percentage of dead cells was assessed using DAPI staining. We added tween (0,1 % Tween-20) to target cells and used it as positive control for NK killing function and target cells alone were used as negative control (19). The list of antibodies used in our experiment are shown in Table I.

Figure 2.
Figure 2.

The gating strategy of dNK cell selection. Fresh, term placentas were collected from the surgery room. After the procession of the fresh, term placenta, the leukocytes were separated from the cell suspension using a tissue processor [gentleMACS Dissociator® (Miltenyi Biotec)] and Accutase® enzyme (Accutase Cell Detachment Solution, Biolegend). The dead cells are excluded by DAPI staining. Among the leukocytes the CD3−, CD14−, CD15− negative cells are selected as NK cells. The CD 56 bright, CD16− cells were identified as dNKs. We can also observe the isotype controls for the two main antibodies used for CD 56 diminished/bright and CD16+/− distinction.

View this table:
Table I.

Antibodies used in the experiment.

Results

In each experiment, approximately 3 million dNK cells were acquired from 20 g of fresh, end term placenta. The selected NK phenotype was assessed before addition to the previously seeded trophoblastic cell lines and after one day and five days of co-culturing. The phenotype of the dNKs before the co-culturing and after 1 and 5 days are shown in Figure 3A and Table II. We found that the original CD56 bright, CD16− phenotype was preserved after one day of co-culturing with both trophoblastic cell lines and after 5 days of exposure to HTR-8 cells or OVCAR3 cells. In contrast, there was an appearance of a CD56 diminished, CD16+ NK population (44.1%) next to the CD56 bright, CD16− pool (55.1%) after the 5-day long exposure to Jeg-3 (Figure 3B). The dNK cells that were re-sorted after 1 day from the co-culture showed decreased cytotoxicity compared to the control not exposed dNK cells. After 1 day the percentage of dead target cells were 29.4% at the 5 to 1 ratio and 16.8% at the 2.5 to 1 ratio in the case of dNK cells co-cultured with HTR-8 cells and 29.6% at the 5 to 1 ratio and 17.3% at the 2.5 to 1 ratio when dNK cells were exposed to Jeg-3. On the 5th day, the percentage of dead target cells was 13.4% at the 5 to 1 ratio and 6.83% at the 2.5 to 1 ratio in the case of dNK cells co-cultured with HTR-8 cells, compared to 5.48% and 4.84%, respectively, at the 2.5 to 1 ratio when dNK cells were exposed to Jeg-3. dNK cells showed significantly reduced cytotoxicity after being exposed to trophoblastic cell lines. No significant difference was observed in the reduction of cytotoxicity between the different types of trophoblastic cell lines (HTR-8 or Jeg-3) (Figure 4). Control NK cells not exposed to any trophoblastic cell line killed at 70.21% of target cells at the 5 to 1 and 54.9% at the 2.5 to 1 ratio on day 1, and 68.43% at the 5 to 1 and 50.1% at the 2.5 to 1 on day 5. See statistical analysis in Table III.

Figure 3.
Figure 3.
Figure 3.

Phenotypic analysis of the dNK cells. A) The phenotype of dNKs before and after the exposure to trophoblastic cells. Live/dead distinction was made by DAPI staining. We can see no significant changes in the dNK phenotype after 1 and 5-day long exposure to HTR-8 cells or OVCAR cells. The 1-day long exposure to Jeg-3 didn’t alter the dNK phenotype but after 5 days a CD 56 diminished, CD16+ population appeared with a similar phenotype to the peripheral NKs. B) Viability of dNK cells. Here we can observe the percentage of CD16+ and CD16− dNK cells among the CD56 bright dNK population. We also provide the flow-cytometry analysis of the DAPI −/+ dNK cells form measuring the live/dead ratio after the co-culturing.

View this table:
Table II.

Change of phenotype of NK cells after exposure to different cell lines. OVCAR cells were used as controls.

Figure 4.
Figure 4.

The changes in dNK cytotoxicity after exposure to different trophoblastic cells. The changes are similar after the 1-day long exposure in case of both cell lines. After 5 days, a significant depression of dNK cytotoxicity is shown after exposure to Jeg-3 compared to HTR-8 at 5 to 1 ratio. The controls are: K 562 cells in Tween −20 0.1% culture media. Standard error (SE) is indicated.

View this table:
Table III.

Change of cytotoxicity of NK cells after exposure to different cell lines.

Discussion

In this study, we attempted to provide a more accurate in vitro model for the interaction of dNK cells with different types of trophoblastic cells. In vitro studies on trophoblastic cell lines and NK cell co-culturing usually use peripheral NK cells or NK cell lines (e.g., MI92) (15, 20). Our protocol for dNK cell extraction from end term, healthy human placenta provided us with a high number of live NK cells with a decidual phenotype (16). We selected the HTR-8 and Jeg-3 cell lines for the in vitro model of normal eVT and choriocarcinoma. Healthy trophoblastic cells present a wide variety of cell surface antigens to modulate the host’s (mother) local immune response. Some of them are direct immune suppressors and some activate specific immune cell functions such as cytokine production. These suppressive and activating mechanisms permit the invasion of the eVT into the myometrium (4). This is an “organized and regulated” invasion in contrast to the spreading of choriocarcinoma. Our data suggests that choriocarcinoma may exaggerate these features.

CD16 is a member of the immunoglobulin superfamily involved in the cell mediated antibody-dependent cellular cytotoxicity (21). It has a pivotal role in initiating lysis by NK cells but it can be also found on the surface of neutrophils, monocytes, macrophages and T- cells (22). NK cells are associated with the CD16A subtype of cluster of differentiation. We hypothesized that there would be an alteration of dNK cell phenotypes after the exposure to different trophoblastic cell lines as the immunological interaction between the trophoblastic cells and the NK cells might alter the cytotoxicity and so the phenotype of the latter. We found increased CD16 expression in dNK cells that were exposed to Jeg-3 for five days. Pongcharoen et al. found that Jeg-3 cell culture supernatant decreased IFN-γ production and expression in leukocytes (23). Previous studies also showed the modulation of IFN-γ production by leukocytes including NK cells after exposure to trophoblastic cells (24). It is also known that IFN-γ production and CD107a up regulation are associated with the loss of CD16 expression in NK cells (25).

The lack of IFN-γ may not lead directly to the increased expression of CD16 but it does not inhibit the appearance or reappearance of a CD16+ population of NK cells. Our results showed similar suppression of dNK cell cytotoxicity after 1 day of exposure to both trophoblastic cell types. After five days, the suppression of the dNK cytotoxicity seemed to be more significant in dNK cells exposed to Jeg-3 than to HTR-8. In this case there a new ‘peripheral NK like’ phenotype of dNK cells sorted back from the plate after the 5th day appeared. The dNK cytotoxicity was significantly reduced after the exposure to both trophoblastic cell lines but the difference between the reduction induced by HTR-8 and Jeg-3 was only significant at the 5:1 ratio and on the 5th day of the exposure. While the aggressiveness of NK cells is generally linked to CD16 positivity, it is important to remember that their overall cytotoxic activity is only partly based on the level of expression of CD16.

We recognize limitations in the study design. The experimental conditions would have been closer to in vivo conditions if first trimester trophoblastic cells had been isolated rather than using cell lines. During our study we were unable to access healthy placental tissue samples from the first trimester due to institutional restrictions. However, healthy, end term placental tissue was available but were unable to reproduce a reliable protocol for primary trophoblastic cell isolation and culture from fresh, term placenta. Moreover, the structure and physiology of the term placenta differ from the early placenta that is still under the process of placentation (26), which is why we used trophoblastic cell lines available from commercial cell banks. During the physiological invasion by eVTs, the trophoblastic cells do not form a monolayer as they do in cell culture. These changes may affect the dynamics of the immunological interaction between dNKs and trophoblastic cells. Finally, we were only able to perform cocultures for five days. The 5-day long exposure time was established because both trophoblastic cell lines can overgrow in the 6 well plate on the 6th day affecting the cell function and viability.

The study has several unique strengths. Regarding the choriocarcinoma cell lines, we selected Jeg-3 because both Jeg-3 and the eVT derived HTR-8 have the same HLA expression pattern as they both express HLA G, C and E on their surface in contrast to other non eVT derived cell lines (27). HTR-8 cells are not identical to the invading eVT cells as they are immortalized by simian viral transfection but they have been isolated from explant cultures of first trimester human placenta at the 8th-10th weeks of pregnancy (17). We also used a different cancer cell line, OVCAR-3 cells (derived from ovarian adenocarcinoma) as a negative control to be used for co-culture and compare it with the trophoblastic cells. Based on our results, reduced cytotoxicity of dNK cells induced by Jeg-3 appears to be unique to choriocarcinoma and not a generalized effect of cancer.

Conclusion

While dNK cells undergo various changes in their function after being exposed to the invading eVTs, and alteration of their cytotoxicity is only one of them. The alteration of the NK phenotype, combined with decreased cytotoxicity of those exposed to Jeg-3 supports our original hypothesis that the choriocarcinoma tissue creates a more suppressive microenvironment for NK cytotoxicity. Unraveling the nature and exact mechanism of this effect will be an important direction for future study (28).

Acknowledgements

The Authors would like to acknowledge the continuous assistance of Grigoriy Losyev from the Brigham and Women’s Hospital Flow Cytometry Laboratory.

Footnotes

  • Authors’ Contributions

    Conceptualization: Kornél Lakatos, Kevin Elias, György Végh. Data curation: Kornél Lakatos. Formal Analysis: Kornél Lakatos. Funding Acquisition: Kevin Elias, Ross Stuart Berkowitz. Investigation: Kornél Lakatos. Methodology: Kornél Lakatos, Kathleen Hasselblatt, Thomas McElrath. Project Administration: Kornél Lakatos, Kevin Elias. Resources: Kevin Elias, Kathleen Hasselblatt. Supervision: Kevin Elias, Ross Stuart Berkowitz, Vilmos Fülöp. Validation: Vilmos Fülöp. Visualization: Kornél Lakatos. Original Writing: Kornél Lakatos. Review/Editing: Kornél Lakatos, Vilmos Fülöp.

  • Conflicts of Interest

    The Authors have no conflicts of interest in relation to this study.

  • Funding

    Supported by the Donald P. Goldstein MD Trophoblastic Tumor Registry Endowment, the Dyett Family Trophoblastic Disease Research and Registry Endowment, and the Keith Higgins and the Andrew S. Higgins Research Fund at Brigham and Women’s Hospital.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received June 19, 2025.
  • Revision received August 9, 2025.
  • Accepted August 11, 2025.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Phenotypic Alteration and Suppression of Cytotoxicity of Decidual NK Cells After Co-culturing With Different Trophoblastic Cell Lines
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