The Prognostic Significance of Programmed Death Ligand-1 Expression in pT2/3N0M0 Esophageal Squamous Cell Carcinoma
Received Date: Aug 18, 2018 / Accepted Date: Oct 10, 2018 / Published Date: Oct 12, 2018
Programmed death ligand-1 (PD-L1) is closely related to the prognosis in most of the carcinomas, yet little is available in Esophageal Squamous Cell Cancer (ESCC). The purpose of this study was designed to investigate the prognostic value and clinical significance of PD-L1 in ESCC. The expression of PD-L1 was analyzed by immunohistochemistry (IHC) in 207 esophageal squamous cell cancer cases. Those people were excluded from the study, who had received neoadjuvant chemotherapy or radiotherapy. Follow-up duration ranged from 3 to 164 months, with a mean of 68.2 months. Kaplan–Meier and univariate and multivariate Cox proportional hazards were used to analysis. The levels of PD-L1 expression were higher in ESCC lesions than in the paired noncancerous tissues. The IHC analysis showed the expression level of PD-L1 was highly expressed in 79 (38.1%) cases. The expression of PD-L1 was not correlated with smoking status, the T stage, histological classification, SCCA and differentiation. Patients with higher level of PD-L1 showed poorer cancer special survival. PD-L1 expression may be a risk factor for the patients’ survival. This novel study identifies PD-L1 not only as a useful biomarker to diagnose and determine the prognosis of stage IIA ESCC, but also as a potential therapeutic target for patients with ESCC. This study has been approved by the Research Data Deposit its number is RDDA 2018000591.
Keywords: Programmed death ligand-1; ESCC; Immunohistochemistry; Prognosis; Biomarker; Esophageal; Squamous cell cancer
In worldwide, Esophageal cancer is one of the most common malignancies, which ranks sixth in terms of cancer-related mortality. There are about 400,000 cases die of the carcinoma [1,2]. It’s prevalent in these countries, China, Iran, South Africa, Uruguay, France, and Italy. However, almost half of new esophageal cancer cases occur in China, which results in the highest mortality rate [3-5]In China, importantly, squamous cell carcinoma is the major histological subtype, which accounts for >95% of esophageal cancer cases . At present the treatment of esophageal cancer mainly including surgery, radiotherapy and chemotherapy, surgery is the main treatment [7,8]. Despite improvements in minimally invasive treatment strategies, surgery remains the mainstream of curative management. For esophageal cancer, unfortunately, the outcome of surgical resection remains poor, in China, a postoperative 5-year survival rate of only 20% to 40% [9,10]. So, to improve the cancer special survival of patients with esophageal cancer, still need to explore new treatment strategies or drug therapeutic targets.
Existing research indicate those closely related to the occurrence of esophageal cancer and the progress factors are: clinical stage, drinking, smoking, body mass index (BMI), dietary habits, and so on. Because of the lack of understanding of the pathogenic mechanism of esophageal cancer and there are no effective molecular predictors, the clinical diagnosis and treatment in patients with ESCC is difficult to improve. As human biomedical has entered into the time of molecular genetics, it cannot satisfy the needs of oncology research just rely on the traditional clinical characteristics and pathological morphology research, it is urgently needing to use molecular diagnostic techniques to find the mechanism of occurrence and development of tumor pathology for the decision of the prognosis and treatment of tumor. Scientific and accurate staging system and individualized prognosis prediction can help us to correctly select poor prognosis of patients with high recurrence metastasis tendency, the multi-disciplinary comprehensive treatment and their reasonable and effective, which is of great significance for the improvement of esophageal cancer curative effect.
Programmed death ligand-1 (PD-L1) is a transmembrane glycoprotein, composed of 290 amino acids belongs to B7-CD28 members of the family. The Tumor antigen specific T cells induced apoptosis is the main mechanism in the tumor cell immune escape, PL-L1 is negative synergy to stimulate the members of the family of molecules, then it plays an important role after combining with PD-1 receptor binding specificity in induced T cell apoptosis [11,12]. There are a lot of studies reported that PD-L1 expression has been detected in breast cancer, lung cancer, gastric cancer, colorectal cancer, esophageal cancer, ovarian cancer, cervical cancer, kidney cancer, bladder cancer, pancreatic cancer, glioma, and melanoma in human tumor tissue, and the expression level of PD-L1 is closely related with the patient's clinical significance [13-19]. Our study is to observe the expression and clinical significance of PD-L1 in stage IIA ESCC tissue and explore the relationship between the expression level of PDL1 in tumor tissue with the clinicopathological factors of esophageal squamous carcinoma, further to explore whether the PD-L1 could become A molecular biological indicator of ESCC immunotherapy.
Materials and Methods
A total of 207 patients retrospectively enrolled in the present study who underwent esophagectomy at the Department of Thoracic Surgery of Sun Yat-Sen University Cancer Center (Guangzhou, China) between August 2000 and October 2010. Patients eligible for this cohort study had pathologically confirmed stage IIA ESCC. Patients were excluded if they had previously received cytotoxic chemotherapy or radiotherapy or immune checkpoint inhibitors or underwent other immune therapy regimens or had a past or current history of another malignancy. It’s not eligible that patients’ tumors were located at the esophagogastric junction or cervical esophagus or had other histological subtypes of esophageal cancer besides ESCC. Patients didn’t exhibit clinical evidence of infection or other inflammatory conditions, and none received preoperative immune therapy or irradiation or chemotherapy. All patients, certainly, were staged according to the 7th Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. The Ethics Committee of Sun Yat-Sen University Cancer Center approved the study’s protocol.
There were the standard surgical approaches, the Sweet (left thoracotomy and diaphragm incision), the McKeown (right thoracotomy, laparotomy, and neck incision), and the Ivor Lewis (laparotomy and right thoracotomy) procedures. In this cohort of patients, thoracoabdominal lymphadenectomy was performed.
We recommend that patients come to the outpatient department for follow-up examination every 3 months for the first 2 years, then every 6 months for the next 3 years, and then every year after that. Follow-up examinations consisted of history taking, barium esophagography, physical examination, chest radiography, cervical ultrasonography, abdominal ultrasonography, and neck-abdomen CT scans. If necessary, patients underwent positron emission tomography-CT and/or endoscopy.
A total of 207 ESCC tissues and their adjacent non-tumorous samples were performed with an Envision system, in accordance with the manufacturer's instructions (Denmark, Glostrup, Dako): The slides were deparaffinized in dimethylbenzene and rehydrated with graded alcohol (100%, 95%, 75%) prior to antigen retrieval with sodium citrate (Sangon Biotech Co., Ltd., Shanghai, China) and blocking of the endogenous peroxidase activity with 0.3% hydrogen peroxide (Sangon Biotech Co., Ltd.). Then the slides were incubated overnight with a polyclonal rabbit PD-L1 antibody (1:100; Cell Signaling Technology, Beverly, MA) at 4°C, followed by a 30 min incubation period with Ventana Omni Mapanti-rabbit secondary antibody at room temperature. Next, the slides were rinsed with phosphate-buffered saline, then incubated with 3, 3'-diaminobenzidine for 1 min, counterstained with hematoxylin, dehydrated using graded alcohol (90%, 95%, and 100%) sequentially and mounted. After IHC staining, in the slides, digital images of each spot were captured at a magnification of 400x, 200x and 100x, which used a DMI4000B inverted research microscope (Leica Microsystems GmbH, Wetzlar, Germany). The two pathologists examined all slides independently, and they had no prior knowledge of the clinical parameters of the patient. The intensity of staining was scored from 0 to 3, and the extent of staining was scored from 0 to 4 (0% for 0; 1%-10% for 1 point; 11%-25% for 2 points; 26%-40% for three points; >41% for 4 points). The final quantitation of each staining was obtained by multiplying the two scores. According to the patients’ clinicopathological data, we used an open source software, which termed X-tile program, version 3.6.1 (School of Medicine, Yale University, New Haven, CT, USA) to optimize the cutoff value of the PD-L1 expression index .
Statistical analysis was performed using SPSS Statistics 17.0 software (IBM SPSS, Inc., Chicago, IL, USA). The multivariate logistic regression analysis calculated odds ratios (OR) with 95% confidence intervals (95% CIs). Multivariate analysis was performed to explore the influences of maximum tumor diameter, SCC-Ag levels, sex, intraoperative blood loss, age, history of alcohol consumption and smoking history on cancer special survival (CSS). A two-sided p<0.05 was considered statistically significant. The multivariate analysis confirmed the most valuable prognostic factors in univariate analysis. The other confounding factors which affected survival were eliminated by multivariate Cox regression analysis. The selected variables with univariate analysis was p<0.05. Similarly, log-rank tests and Kaplan– Meier analysis were used to compare survival curves between groups. Cases were censored at the end of follow-up or death.
Of the 207 enrolled patients, 159 (76.8%) were males and 48 (23.2%) were females, whose age range from 37 years to 81 years (median, 60 years). The 3- and 5-years cancer special survival rates are 70.5% and 63.3% respectively. The mean time from the operation to the last censoring date was 66 months. The last follow-up time of this group of patients is June 2015, the followed-up time is 3 months to 164 months, the average (68.2 ± 62.5) months. During the operation, we dissected the number of lymph nodes between 0-19 with 125 patients, between 20-39 with 68 patients, between 40-59 with 9 patients and between 60-79 with 4 patients. They accounted for 56.4%, 32.9%, 4.3%, and 2.0%, respectively. One patient’s data is lost. The mean number of lymph node dissections was 19.13, the median lymph node dissection was 15.50, and the mode number was 14. There was no pathological diagnosis of lymph node metastases.
Patients’ clinical characteristics and PD-L1 expression
To elucidate the biological significance of PD-L1 in ESCC, we examined the immunohistochemical expression of PD-L1 in 207 ESCC specimens, as compared with the levels in matched adjacent nontumorous esophageal tissues. The results revealed that PD-L1 was primarily localized in the cytoplasm of tumor cells (Figure 1).
Figure 1: Immunohistochemistry (IHC) assays of PD-L1 expression in 207 paired ESCC tissues. The upper left and right panel represents low and high PD-L1 expression in ESCC. Lower panels represent magnified pictures of boxed area in the corresponding upper panels. The full line and dotted line scale bar represents 50 μm and 10 μm, respective.
High PD-L1 expression was found in 79 of the 207 (38.2%) primary ESCC specimens, compared with 128/207 (61.8%) in adjacent nontumorous tissues (Figure 1). We compared staining of tumor and nontumor tissues and found that the expression of PD-L1 in tumor tissues was higher than that in nontumor tissues. These data showed that PDL1 expression was significantly higher in ESCC tissues than that in adjacent non-tumorous tissues.
We correlated PD-L1 status in 207 ESCC samples with widely recognized clinicopathological features to verify the functions of PDL1 in ESCC. The expression of PD-L1 displayed that there was no association with age, gender, smoking status, drinking status, differentiation, T stage, BMI, tumor length, surgery approach, blood losing, SCCA (all p>0.05) (Table 1).
|Characteristics||PD-L1 Expression: No. of patients (%)||p-valueb (χ2 test)|
|Low (128)||High (79)|
|Male||94 (59.1)||65 (40.9)||0.097|
|Female||34 (70.8)||14 (29.2)|
|≤ 60||70 (60.9)||45 (39.1)||0.431|
|>60||58 (63)||34 (37)|
|No||51 (66.2)||26 (33.8)||0.197|
|Yes||77 (59.2)||53 (40.8)|
|Well–moderate||104 (61.9)||64 (38.1)||0.552|
|Poor||24 (61.5)||15 (38.5)|
|T2||48 (65.8)||25 (34.2)||0.241|
|T3||80 (59.7)||54 (40.3)|
|underweight (<18.5 kg/m2)||83 (64.5)||58 (35.5)||0.370|
|Normal weight (18.5 to 24.9 kg/m2)||45 (58.9)||51 (41.1)|
|Tumor length (cm)|
|≤ 5||111 (61.3)||70 (38.7)||0.169|
|>5||17 (65.4)||9 (34.6)|
|Approach of Surgery|
|Left thorax||93 (62.0)||57 (38.0)||0.530|
|Right thorax||35 (61.4)||22 (38.6)|
|Blood lose (ml)|
|≤ 200||99 (63.1)||58 (36.9)||0.316|
|>200||29 (58.0)||21 (42.0)|
|≤ 1.5||115 (62.5)||69 (37.5)||0.367|
|>1.5||13 (56.5)||10 (43.5)|
Table 1: Correlation between PD-L1 expression and clinicopathological characteristics.
Expression of PD-L1 significantly associated with prognosis in ESCC patients
Our results indicated that cancer-specific survival (CSS) in Group low expression was significantly higher than that in Group overexpression (p<0.001; Figure 2). Patients in Group low expression exhibited significantly better 3- and 5-year survival rates (0.937 and 0.726, respectively) than those in Group overexpression (0.824 and 0.605, respectively).
The correlations between CSS and clinical characteristics were identified by multivariate and univariate analyses. As shown in Table 2, univariate analyses indicated that the following clinical characteristics were significant prognostic factors for CSS in patients with esophageal cancer: T stage [hazard risk (HR)=1.755; 95% CI=1.105-2.785; p=0.017]; PD-L1 expression (HR=5.514; 95% CI=3.564-8.532; p=0.001). Further multivariate analysis based on the previously mentioned parameters confirmed that only T stage (p=0.027) and PDL1 expression (p=0.005) were independent prognostic factors. Our study revealed that the expression of PD-L1 significantly associated with prognosis in ESCC patients, it is a useful predictor of postoperative outcome in this group of patients.
In addition, we process subgroup analyses according to the patients’ clinical pathological characteristics and found that the expression levels of PD-L1 significantly associated with prognosis in ESCC patients (Table 2). Especially in the state of patients' gender, age, differentiation, T stage, smoking status, drinking status, surgical approach and body mass index of each subgroup of patients with a high level of PD-L1 expression and shorter survival time were statistically significant correlation.
|Characteristics||Univariate analysis||Multivariate analysis|
|HR||95% CI||p-Value||HR||95% CI||p-Value|
|= 5/>5 (cm)||1.207||0.671-2.172||0.531||--||--||--|
|Blood lose (ml)|
Table 2: Univariate and multivariate analysis of potential prognostic parameter PD-L1 for 207 ESCC patients regarding cancer special survival.
Discussion and Conclusion
The occurrence and development of malignant tumor is a very complicated process, the specific T cell in the antitumor immune response, have a vital role in the immune response. If the T cells could work successfully depends on a variety of coordinating stimulus molecule by ligand and receptor binding to provide coordinated stimulus signal. What are now known to coordinated stimulus family including the B7 family (immunoglobulin super family), TNF family and cytokines. PD-L1/PD-1 as B7/CD28 coordinated stimulus molecule super important members of the family has been confirmed by inhibiting proliferation and activation of T cells to negatively regulate immune response and play a role in the tumor immune escape response [21,22].
This research uses the immunohistochemical to detect the expression of PD-L1 in stage IIA esophageal squamous cell carcinomas, found that the expression of PD-L1 in tumor tissues is higher than tissue adjacent to carcinoma and normal esophageal tissue. Survival analyses have showed that patients with esophageal cancer primary lesion high expression of PD-L1 are associated with poor cancer-specific survival. Our research provides strong evidence for PD-L1 high expression level associated with adverse outcomes for patients with esophageal cancer and suggests that the PD-L1 expression level is an independent prognostic marker in patients with esophageal cancer.
According to a meta-analysis in 1157 NSCLC patients, patients with PD-L1 positive expression have shorter overall survival (p<0.01) . In addition, there are several studies have found that the PD-L1 in the case of positive expression in tumor tissues is closely related to the prognosis [24-27]. The studies about PD-L1 expression in esophageal cancer also have confirmed that the results are consistent with this study before [28,29].
At present, the immunotherapy of cancer has become an important effective treatment following surgery, radiation and chemotherapy. Through the resistance against PD-L1 and PD-L1 antibody blocking PD-1/PD-L1 signaling pathway in lung cancer, melanoma, highlighted in a variety of late malignant tumor treatment curative effect. The earliest clinical trials using on the human body immune therapy is used to treat melanoma, the results showed that resistance to PD-1 enhances the objective response rate of melanoma patients . Results of using PD-L1 antibody to treat include non-small cell lung cancer in the progress tumor clinical research show that the obvious extension of progression-free survival in patients with advanced tumor . Professor Brahmer used PD-1 antibodies Nivolumab to treat lung cancer patients, patients with PD-L1 positive objective response rate is higher than PD-L1 negative patients. The studies suggest that, blocking the PD-1/PD-L1 signaling pathway is a new kind of tumor immune targeted treatment strategy. Therefore, in future PD-L1 could become a prognosis judgment index and a new target for immunotherapy in esophageal squamous carcinoma. The deficiency also existing in this research, our study is a single institution research. Because the main pathological type for patients with esophageal squamous cell carcinomas in China, this study didn't involve adenocarcinoma. Only the stage IIA esophageal cancer patients were enrolled. This study did not delve into the molecular pathological mechanism of PD-L1 in the occurrence, evade the adaptive immunity, invasion and metastasis in the esophageal cancer.
The expression of PD-L1 in primary esophageal squamous carcinoma tissue expression levels higher than normal tissue adjacent to carcinoma, the expression of PD-L1 in tumor tissue level may be an independent prognostic factor for esophageal squamous cell carcinoma.
The study protocol was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center.
This work was supported by the Science and Technology Planning Project of Guangdong Province, China (No. 2012B031800463) and the Science and Technology Planning Project of Guangdong Province, China (No. 2013B022000040).
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Citation: Ma Q, Jiang F, Wu L, Liu W, Jia R, et al. (2018) The Prognostic Significance of Programmed Death Ligand-1 Expression in pT2/3N0M0 Esophageal Squamous Cell Carcinoma. J Cancer Sci Ther 10: 302-307. DOI: 10.4172/1948-5956.1000560
Copyright: © 2018 Ma Q, et al. This is an open-access article distributed under the terms of the creative common’s attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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