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Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1063-1069

Expression of programmed death-ligand 1 and hypoxia-inducible factor-1α proteins in endometrial carcinoma

1 Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt
2 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Al Menoufia, Egypt

Date of Web Publication11-Dec-2018

Correspondence Address:
Ashraf Ishak Fawzy Tawadros
Fawzy Tawadros, Department of Pathology, Faculty of Medicine, Minia University, Minia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.202891

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 > Abstract 

Background: Programmed death-ligand 1 (PD-L1) and hypoxia-inducible factor-1α (HIF-1α) proteins mediate major alterations of tumor microenvironment including generation of immunosuppressive microenvironment and tumor hypoxia, respectively. These alterations play a crucial role in carcinogenesis and tumor progression.
Aims: The present study was designed to investigate the correlation between the expression of PD-L1 and HIF-1α proteins and the clinicopathologic variables in endometrial carcinoma.
Materials and Methods: Tumor tissue sections from 95 endometrial carcinomas were evaluated for PD-L1 and HIF-1α immunohistochemical protein expression.
Statistical Analysis Used: The statistical analyses were performed using Chi-square and Fisher's exact tests when appropriate. Two-sided P < 0.05 was considered statistically significant.
Results: PD-L1 and HIF-1α expression were detected in 48.4% and 68.4% of endometrial carcinomas, respectively. PD-L1 expression was significantly associated with lymph node metastasis (P = 0.027). HIF-1α expression was significantly associated with tumor grade, depth of myometrial invasion, and lymph node metastasis (P = 0.014, 0.012, and 0.046, respectively). A significant positive correlation was detected between PD-L1 and HIF-1α immunoexpression (P = 0.015).
Conclusions: PD-L1 and HIF-1α proteins are promising potential prognostic biomarkers in endometrial carcinomas since their overexpression is associated with clinicopathologic variables of advanced disease. A potential role of HIF-1α in upregulation of PD-L1 expression is suggested based on the finding of positive correlation between PD-L1 and HIF-1α expression in endometrial carcinoma. These findings point to a potential role of biomarkers inhibitors in controlling endometrial cancer progression.

Keywords: Clinicopathologic variables, endometrial carcinoma, hypoxia-inducible factor-1α, immunohistochemistry, programmed death-ligand 1

How to cite this article:
Tawadros AI, Khalafalla MM. Expression of programmed death-ligand 1 and hypoxia-inducible factor-1α proteins in endometrial carcinoma. J Can Res Ther 2018;14, Suppl S5:1063-9

How to cite this URL:
Tawadros AI, Khalafalla MM. Expression of programmed death-ligand 1 and hypoxia-inducible factor-1α proteins in endometrial carcinoma. J Can Res Ther [serial online] 2018 [cited 2020 Apr 7];14:1063-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1063/202891

 > Introduction Top

Endometrial carcinoma is the most common gynecologic malignancy. It is pathologically classified into two groups, Type I (endometrioid endometrial carcinoma, [EEC]) accounting for 70%–80% of cases and Type II (non-EEC) including serous and clear cell carcinomas. The 5-year overall survival rate for EECs ranges from 75% to 86% while that of non-EECs is only 35%.[1] Thus, understanding the molecular changes underlying endometrial carcinogenesis and progression might be helpful in identification of new molecular therapeutic targets which may be beneficial in controlling tumor progression and improving the survival rate.

Alterations of tumor microenvironment play a crucial role in the process of tumorigenesis and tumor progression. One of the most important alterations is the generation of immune-suppressive microenvironment by cancer cells leading to tumor escape from the host immune system and thereby, enhancing tumor cell survival, proliferation, migration, and invasion.[2] Overexpression of immune checkpoints is an important mechanism mediating immune-suppressive microenvironment. These checkpoints are a variety of inhibitory pathways which are normally employed by the immune system to maintain self-tolerance and minimize collateral damage during physiologic responses to pathogens. Programmed death 1 (PD-1)/PD ligand-1 (PD-L1) pathway is a major immune checkpoint involved in the suppression of T-cell function and the restriction of tumor cell killing leading to cancer progression.[3] PD-L1 (B7-H1, CD274) is upregulated in various malignancies, and its overexpression has been linked to worse prognosis and resistance to anti-cancer therapies in many of these tumors.[4]

Hypoxia is another common alteration occurring in the tumor microenvironment of solid malignancies owing to imbalance between rapid growth of tumors and their blood supply.[5] Increasing evidence has demonstrated that hypoxia is playing a key role in emergence of a more aggressive phenotype with increased invasiveness, metastatic potential, and poor survival. Moreover, hypoxia has been shown to induce resistance to chemotherapy and radiotherapy.[6] Hypoxia-inducible factor-1 (HIF-1) is the master regulator of cell adaptation to hypoxia. It is a heterodimeric transcription factor composed of the subunits HIF-1α and HIF-1β. HIF-1α is the main functional protein of HIF-1 complex.[7] Upregulation of HIF-1α has been observed in a wide variety of human cancers where it has been shown to be correlated with metastatic potential and poor prognosis.[8]

The present study was carried out to study the correlation between PD-L1 and HIF-1α expression and their correlation with clinicopathologic variables in endometrial carcinomas utilizing immunohistochemical technique.

 > Materials and Methods Top

Study design

The present study was conducted on paraffin blocks of formalin-fixed tissue sections of 95 endometrial carcinoma specimens distributed as 78 EEC and 17 non-EEC distributed as 14 serous carcinoma and three clear cell carcinoma. These specimens were retrieved mainly from the archives of histopathology laboratory of Minia University Hospital. Some cases are collected from private laboratories. The specimens were obtained from randomly selected patients who underwent total abdominal hysterectomy, with bilateral salpingo-oophorectomy and pelvic lymph node dissection during the period from 2008 to 2014. The presence of distant metastasis was excluded by abdominal computerized tomography scans, X-rays of the lungs and bone scans before the surgical intervention. All investigated cases did not receive preoperative chemotherapy or radiotherapy. The histopathologic diagnosis and grading of cancer cases were revised by the author. Investigated EEC cases were categorized into Grade I (well-differentiated), II (moderately differentiated), and III (poorly differentiated) based on WHO classification of histologic differentiation. Serous and clear cell carcinomas are high-grade by definition. All carcinomas were staged according to the International Federation of Gynecology and Obstetrics (FIGO) criteria.[9] Age of patients ranged from 38 to 79 years with mean age 54.6 ± 1.1 years. The patient and tumor characteristics of investigated cases were shown in [Table 1].
Table 1: Patients and tumor characteristics

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Immunohistochemical staining

Immunohistochemical staining was performed on 4-μm thick sections. These sections were deparaffinized in xylene, rehydrated in descending grades of alcohol, and washed in phosphate-buffered saline (PBS) (pH 7.2). Sections were incubated with 3% hydrogen peroxide in methanol for 15 min after heat-induced antigen retrieval (five 3-min microwave oven passages at 750 W in 10 mM sodium citrate buffer, pH 6.0). Then, sections were incubated for overnight at 4°C with primary antibodies against PD-L1 (dilution 1:100, rabbit monoclonal [clone EPR1161 (2)], Abcam, Cambridge, UK) and HIF-1α (dilution 1:100, mouse monoclonal [clone 28b], Santa Cruz Biotechnology, Santa Cruz, CA, USA). After washing in PBS, sections were incubated with biotin-labeled secondary antibody and then with streptavidin-horseradish peroxidase using the DAKO universal LSAB2/HRP kit (DAKO, Glostrup, Denmark) at room temperature for 30 min for each step. 3,3'-diaminobenzidine was used as chromogen and hematoxylin as the nuclear counterstain. Negative control was performed by omission of primary antibodies and replacement by PBS. Human placenta served as positive control for PD-L1 while urothelial lining of human urinary bladder was employed as positive control for HIF-1α.

Interpretation of immunohistochemistry results

Positive immunostaining of PD-L1 was membranous, and HIF-1α was nuclear. Positive cases were classified according to the rate (percentage) of positive cell staining (R) on the one hand and their staining intensity (I) on the other hand. Immunostaining of <10% of tumor cells is categorized as 0, immunostaining of 10%–25% of tumor cells as 1, staining of 26%–50% of tumor cells as 2, staining of 51%–75% as 3, and staining of >75% as 4. The staining intensity in each specimen was categorized as 1, 2, and 3 (weak, moderate, or strong, respectively). The total immunostaining score (I × R) was assigned to each case by multiplying the score for the percentage of positive tumor cells (1–4) by staining intensity score (1–3) resulting in a total score of 1–12. For statistical purposes, the investigated cases were categorized as negative if the total score was <3 and positive if the total score was ≥3.

Statistical analysis

The statistical analyses were performed using SPSS for Windows, version 16.0 (SPSS Inc., Chicago, IL, USA). Chi-square and Fisher's exact tests were used when appropriate to assess the relationships between biomarkers and clinicopathologic variables of included tumors. Two-sided P < 0.05 was considered statistically significant.

 > Results Top

Programmed death-ligand 1 immunohistochemical expression

Positive PD-L1 immunostaining was detected in 46 out of 95 endometrial carcinomas (48.4%) distributed as 39 out of 78 EEC (50%) and seven out of 17 non-EECs (41.2%) including five out of 14 serous carcinomas (35.7%) and two out of three clear cell carcinomas (66.7%). Our study demonstrated a significant correlation between PD-L1 expression and lymph node metastasis. The rate of positive PD-L1 immunostaining in tumors with lymph nodal metastasis (10 out of 13 cases, 76.9%) was higher than in those without nodal metastasis (36 out of 82 cases, 43.9%) (χ2 = 4.899, P = 0.027).

No significant correlation was observed between PD-L1 expression and age (P = 0.237), histologic subtype (P = 0.509), tumor grade (P = 0.203), depth of myometrial invasion (P = 0.384), FIGO stage (P = 0.109), or lymphovascular invasion (LVI) (P = 0.439) [Table 2] and [Figure 1], [Figure 2], [Figure 3].
Table 2: Programmed death-ligand 1 expression and clinicopathologic variables in endometrial carcinomas

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Figure 1: Programmed death-ligand 1 expression in endometrioid endometrial carcinoma ×400

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Figure 2: Programmed death-ligand 1 expression in serous carcinoma (papillary pattern) ×200

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Figure 3: Programmed death-ligand 1 expression in clear cell carcinoma ×400

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Hypoxia-inducible factor-1α immunohistochemical expression

Positive HIF-1α immunostaining was detected in 65 out of 95 investigated cases (68.4%) distributed as 53 out of 78 EEC (67.9%) and 12 out of 17 non-EEC (41.2%) including 10 out of 14 serous carcinomas (71.4%) and two out of three clear cell carcinomas (66.7%). The present study demonstrated a significant positive correlation between HIF-1α immunostaining and higher histologic grades of the EEC since the rate of positive immunostaining was increasing significantly from G1 up to G3. Among 24 well-differentiated (G1) tumors, 11 cases (45.8%) were positive for HIF-1α. In moderately differentiated (G2) tumors, 29 out of 39 cases (74.4%) were positive and in poorly differentiated (G3) tumors, 13 out of 15 cases (86.7%) were positive for HIF-1α (χ2 = 8.539, P = 0.014). Also noted was a significant positive correlation between HIF-1α immunoreactivity and depth of myometrial invasion since the rate of positive immunostaining was higher in tumors invading ≥50% of myometrial thickness than in those invading <50% of the myometrial thickness. In the former group, positive immunostaining was detected in 28 out of 33 cases (84.9%) and in the latter, it was detected in 37 out of 62 cases (59.7%) (χ2 = 6.315, P = 0.012). In addition, a significant positive correlation between HIF-1α expression and lymph node metastasis was found in our study. The rate of positive HIF-1α expression was higher in tumors positive for nodal metastasis (12 out of 13 cases, 92.3%) than in those negative for nodal metastasis (53 out of 82 cases, 64.6%) (χ2 = 3.977, P = 0.046). Meanwhile, no significant correlation was observed between HIF-1α expression and age (P = 0.174), histologic subtype (P = 0. 832), FIGO stage (P = 0.508), and LVI (P = 0.405) [Table 3] and [Figure 4], [Figure 5], [Figure 6].
Table 3: Hypoxia-inducible factor-1α expression and clinicopathologic variables in endometrial carcinomas

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Figure 4: Hypoxia-inducible factor-1α expression in endometrioid endometrial carcinoma ×200

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Figure 5: Hypoxia-inducible factor-1α expression in serous carcinoma (papillary pattern) ×200

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Figure 6: Hypoxia-inducible factor-1α expression in clear cell carcinoma ×200

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The relationship between programmed death-ligand 1 and hypoxia-inducible factor-1α immunoreactivity

The present study demonstrated a significant positive correlation between PD-L1 and HIF-1α immunoreactivity in the investigated endometrial adenocarcinomas (χ2 = 5.957, P = 0.015).

 > Discussion Top

Cancer immunoediting is a complex process referring to the dynamic interaction between tumor cells and host immune system. This process starts by immunosurveillance where the innate immune system recognizes and eliminates tumor cells, mainly through the cytotoxic effect of natural killer, CD4-positive, and CD8-positive T-cells as well as interferon-γ and reactive oxygen species secretion. However, some weakly or nonimmunogenic tumor cells escape the elimination phase and are selected for growth. These tumor cells accumulate further mutations that increase tumor cell adaptation to and evasion the immune response through the generation of an immune suppressive microenvironment, leading to tumor escape and cancer progression.[10]

PD-1/PD-L1 pathway is a major coinhibitory immune checkpoint pathway controlling T-cell function. PD-1 receptor, a member of the CD28 family, is a key immune checkpoint receptor that is expressed on activated T-cells, B-lymphocytes, natural killer cells, dendritic cells, and activated monocytes. Meanwhile, PD-L1 (B7-H1, CD274) is expressed in immunologically privileged sites such as the placenta, retina, spleen, and tonsils as well as in macrophages and dendritic cells. The interaction between PD-1 and its ligands PD-L1 leads to T-cell exhaustion, inactivation, and apoptosis. In addition, this interaction induces cell cycle arrest and inhibits T-cell proliferation. Accordingly, activation of PD-1/PD-L1 pathway mediates peripheral immune tolerance and limits the tissue damage after a sustained immune/inflammatory response.[2],[11]

PD-L1 is upregulated in various malignancies, including nonsmall cell lung cancer, melanoma, glioblastoma, leukemias as well as carcinomas of the ovary, breast, cervix, kidney, esophageal, stomach, colon, pancreas, and liver. Interaction of PD-L1 on both of cancer cells and antigen presenting dendritic cells with PD-1 on tumor infiltrating lymphocytes, macrophages, and myeloid-derived suppressor cells (MDSCs) mediate immune tolerance to malignant cells and facilitate tumor escape leading to cancer progression.[4],[11],[12],[13]

Consistent with these reports, the present study demonstrated PD-L1 overexpression in 48.4% of investigated endometrial carcinomas. Our rate corresponds with the reported range (24.9%–88%) in the literature.[12],[14],[15],[16] This wide range can be explained by different antibodies used with different specificity and sensitivity in addition to different scoring methods and cutoff values for interpretation of immunohistochemical staining results. However, none of these reports have studied the relationship of PD-L1 expression and clinicopathologic variables. We found a significant positive association between PD-L1 expression and lymph node metastasis. Such association was reported with or without other poor prognostic clinicopathologic parameters and poor survival in other malignancies including oral squamous cell carcinoma, breast, lung, gastric, esophageal, and cervical carcinoma.[17],[18],[19],[20],[21],[22]

Hypoxia is another common event in the microenvironment of human malignancies that has been shown to promote progression of transformed cells.[6] HIF-1α plays a major role in mediating adaptive mechanisms of cancer cells to hypoxia. In normoxia, HIF-1α is extremely labile and rapidly degradable with a half-life of <5 min. Hypoxia strongly stabilizes HIF-1α through the inhibition of its rapid degradation by the proteasome and thereby, increasing HIF-1α levels and activity in cells.[7] HIF-1 stabilization may also occur under oxygen-independent conditions, including infection with oncogenic viruses, loss-of-function mutations in tumor suppressor genes, such as Von Hippel-Lindau and p53 and activating mutations of oncogenes as KRAS.[23],[24] In addition, upregulation of HIF-1α can be secondary to increase of its synthesis through activation of PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathways which are triggered by activation of receptor tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], vascular EGFR, HGF, and fibroblast growth factor receptor) or inactivating mutations of PTEN tumor suppressor gene.[8],[24]

Activated HIF-1α induces transcription of over sixty target genes which are essential for cellular adaptive response to hypoxia to maintain cell survival. These genes are implicated in different cellular functions including glucose metabolism, apoptosis, angiogenesis, cell proliferation, cell adhesion and motility, extracellular matrix metabolism, and cell survival. Many of these genes play a crucial role in carcinogenesis and cancer progression.[8]

Upregulation of HIF-1α has been observed in a wide variety of human cancers including carcinomas of oropharynx, colon, stomach, pancreas, cervix, kidney, prostate, and breast where it has been shown to be correlated with aggressive phenotype and poor prognosis.[25],[26],[27],[28],[29],[30],[31],[32]

Similarly, the present study demonstrated HIF-1α overexpression in investigated endometrial carcinomas where it was significantly correlated with advanced clinicopathologic variables including higher histologic grades in EEC, deeper myometrial invasion, and lymph node metastasis. Our findings are concordant with another recent report by Feng et al.[33] In addition, other investigators have reported a significant correlation between HIF-1α and histologic grade in EEC[34],[35] and depth of myometrial invasion.[34],[36] However, in discordance to other reports, we did not find any significant correlation of the biomarker with the histologic subtype of endometrial cancer or FIGO stage[34],[37] which may be attributed to larger number of Type II endometrial carcinomas included in those studies in addition to different antibodies used and different methods of assessment of biomarker expression.

The present study also demonstrated a significant positive correlation between HIF-1α and PD-L1. This correlation has also been shown and explained in a recent molecular study, in which the investigators have found that hypoxia caused a rapid, dramatic, and selective upregulation of PD-L1 on MDSCs, macrophages, dendritic cells, and tumor cells. They provided evidence that this upregulation was dependent on HIF-1α which acts as a major regulator of PD-L1 mRNA and protein expression by directly binds to a transcriptionally active hypoxia-response element in the PD-L1 proximal promoter.[38] Another recent study has demonstrated such positive correlation in human breast and prostate carcinoma cell lines where the investigators have evidenced that the tumor escape mechanism is mediated by upregulation of PD-L1 in a manner dependent on the transcription factor HIF-1α so that knockdown of HIF-1α expression with siRNA has prevented HIF-1α protein accumulation and inhibited the hypoxia-mediated increase in PD-L1 mRNA and cell surface protein levels.[39]

 > Conclusion Top

The present study has demonstrated overexpression of PD-L1 and HIF-1α proteins in investigated cases of endometrial carcinoma using immunohistochemistry. Biomarkers expression was correlated with aggressive clinicopathologic variables including lymph node metastasis (for PD-L1 and HIF-1α) and higher grade and deep myometrial invasion (for HIF-1α). Therefore, we present PD-L1 and HIF-1α proteins as potential prognostic biomarkers in endometrial carcinoma. Also demonstrated in the present study is a potential role of HIF-1α in regulating PD-L1 expression based on a significant positive relationship between both biomarkers. Therapeutic targeting of the alterations in tumor microenvironment using PD-L1 inhibitors with or without HIF-1α inhibitors may be promising in boosting the immune system in cancer patients and preventing or at least limiting cancer progression. Promising results of PD-L1 inhibitors were reported in nonsmall lung cell carcinoma and melanoma therapy.[11] Molecular-based studies will be helpful in establishing the effect of the biomarkers inhibitors on the course and progression of endometrial carcinoma.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2], [Table 3]


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