Prognostic Value of BRAF, Programmed Cell Death 1 (PD1), and PD Ligand 1 (PDL1) Protein Expression in Colon Adenocarcinoma (original) (raw)
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Programmed Cell Death Ligand 1 Expression Is an Independent Prognostic Factor in Colorectal Cancer
Anticancer Research, 2018
Background/Aim: Programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1(PD-L1) axis is associated with immune tolerance via inhibition of T cell activation. The aim of this study was to clarify the significance of PD-1 and PD-L1 expressions and analyze the relationships between PD-1, PD-L1, transforming growth factor-β (TGF-β) and Forkhead box P3 (Foxp3) expressions in colorectal cancer (CRC). Patients and Methods: A total of 116 patients who underwent curative colectomy for stage II/III CRC were included in the study. PD-1, PD-L1, TGFβ, and Foxp3 expressions were examined by immunohistochemistry and related to prognostic factors by Kaplan-Meier. Results: PD-1 expression was correlated with PD-L1, TGF-β, and Foxp3 expressions. Overall survival rates were significantly poorer in the PD-1 and PD-L1-positive groups. Multivariate analysis showed that PD-L1-positive is an independent risk factor. Disease-free survival (DFS) was tended in the PD-L1-positive group. The group with doublepositive expression had significantly poorer prognosis. Conclusion: PD-1 and PD-L1 expressions were associated with a poor prognosis and correlated with TGF-β and Foxp3 expressions in patients with CRC. Colorectal cancer (CRC) is one of the most common cancers worldwide and the fourth most common cancer in Japan (1, 2). More than 1 million new cases were reported annually resulting in about 600.000 deaths worldwide per year (3). Programmed cell death protein 1 (PD-1) is one of the member of B7/CD28 family, first reported in 1992 (4, 5) and expressed in activated immune cells (4, 6). PD-1 has two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Each of them has an additional binding partner, B7-1 for PD-L1 and RGMb for PD-L2 (7, 8). PD-1 and its ligand, programmed cell death ligand 1 (PD-L1), interact to suppress T cells activation in many conditions (9). Recently, the significance of PD-1 or PD-L1 expressions were reported in several types of cancers including rectal cancer, skin cancer, gastric cancer, and breast cancer (10-13). Also, we previously reported PD-1 and PD-L1 expression in gastric cancer after curative resection. PD-1 correlated with poor prognosis and associated with transforming growth factor-β (TGFβ) and Forkhead box P3 (FoxP3) expression. However, little is known about the significance of PD-1 and PD-L1 expression in colorectal cancer. The aim of this study was to investigate the role of PD-1 and PD-L1 expression and analyze the relationships among PD-1, PD-L1, Foxp3, and TGF-β expressions in patients with colorectal cancer.
Clinical impact of programmed cell death ligand 1 expression in colorectal cancer
European Journal of Cancer, 2013
Background: Programmed cell death 1 (PD-1) receptor triggering by PD ligand 1 (PD-L1) inhibits T cell activation. PD-L1 expression was detected in different malignancies and associated with poor prognosis. Therapeutic antibodies inhibiting PD-1/PD-L1 interaction have been developed. Materials and methods: A tissue microarray (n = 1491) including healthy colon mucosa and clinically annotated colorectal cancer (CRC) specimens was stained with two PD-L1 specific antibody preparations. Surgically excised CRC specimens were enzymatically digested and analysed for cluster of differentiation 8 (CD8) and PD-1 expression. Results: Strong PD-L1 expression was observed in 37% of mismatch repair (MMR)-proficient and in 29% of MMR-deficient CRC. In MMR-proficient CRC strong PD-L1 expression correlated with infiltration by CD8 + lymphocytes (P = 0.0001) which did not express PD-1. In univariate analysis, strong PD-L1 expression in MMR-proficient CRC was significantly associated with early T stage, absence of lymph node metastases, lower tumour grade, absence of
OncoImmunology
Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] D 0.49; 95% confidence interval [CI] CI 0.35-0.68), and in tumours of the right colon (HR D 0.43; 95% CI 0.25-0.74) and the left colon (HR D 0.28; 95% CI 0.13-0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.
Diagnostic and Pathologic Value of Programmed Death-Ligand 1 Expression in Colon Carcinoma
2020
Objectives: To evaluate the diagnostic value of programmed death-ligand1 expression in colon carcinoma cells and its correlation with different pathological features. Methods: An immunohistochemical study was conducted on 50 cases diagnosed as colon carcinoma over a one year period from October 2018 to October 2019.The paraffin blocks were received from the Pathology Departments, Faculty of Medicine, Cairo University and Misr University for Science and Technology (MUST). The diagnosis of colon carcinoma for all cases was revised using H&E stain. The immunohistochemical expression of programmed deathligand1 was assessed using immune reactive score method. The personal data, clinical details and pathological diagnosis were recorded and correlated with programmed death-ligand1 expression. Results: This study included 50 cases of colon carcinoma. There was a male predominance with female to male ratio 1:1.08.The age of patients was ranged from 30 years to 76 years with mean age 53.3± 11...
Cancer Science, 2017
The programmed death-1/programmed death-ligand 1 (PD-L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD-L1 expression on tumor cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD-L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty-five patients were included in the analysis. PD-L1 expression on TC and tumor-infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow-up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD-L1 expression on TC and 15.3% showed high PD-L1 expression on TIMC. Patients with high PD-L1 expression on TC had significantly shorter disease-free survival (DFS) than patients with low expression (hazard ratio [HR] 2.36; 95% confidence interval [CI], 1.21-4.62; P = 0.012). In addition, patients with high PD-L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16-0.98; P = 0.046). These findings suggest that PD-L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD-L1 expression on TC and TIMC separately in the tumor microenvironment. C olorectal cancer is a major cause of cancer-related death worldwide. (1) In Japan, there were 124 921 new cases of colorectal cancer in 2011 and 48 485 deaths from the disease in 2014, respectively. (2) Multimodality therapy consisting of surgery, chemotherapy and radiotherapy is the main treatment for operable cancer; (3-5) however, the recurrence rate in patients with stage III colorectal cancer remains high. (6) Previous studies have shown that molecular markers, including BRAF, KRAS and tumor mismatch repair (MMR) status, are useful for predicting recurrences in patients with stage III colorectal cancer. (7,8) In addition, the prognostic effect of the immune microenvironment has become increasingly recognized. (9-11) The programmed death 1 (PD-1)/programmed death 1-ligand 1 (PD-L1) signaling pathway is a negative feedback mechanism that suppresses the activity of T cells. (12) PD-L1 expression has been reported on tumor cells or tumor-infiltrating immune cells in several malignancies, including colorectal cancer. (13) Furthermore, it has been suggested that high PD-L1 expression on tumor cells (TC) and/or tumor infiltrating immune cells is associated with prognosis across different tumor types, including esophageal cancer (14,15) and urothelial cancer. (16) However, the prognostic value of PD-L1 expression in patients with stage III colorectal cancer has not yet been established. The aim of the present study was to evaluate the relationship between PD-L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Methods Patients and samples. Formalin-fixed paraffin-embedded block specimens from surgical resection of the primary tumor were obtained from 318 patients with stage III colorectal cancer who underwent curative surgery and adjuvant chemotherapy at our institution between January 2009 and July 2012. We excluded 83 patients who received radiotherapy or chemoradiotherapy before surgery. A total of 235 patients were included in this study, and all of their samples were evaluable for immunohistochemistry (IHC). PD-L1 expression on TC and tumor-infiltrating mononuclear cells (TIMC) as well as the number of CD8 positive T cells were evaluated by IHC. TIMC were distinguished from TC by their morphological features following HE staining. Baseline clinicopathological characteristics and clinical outcome data were retrospectively collected from the Colorectal Cancer Database of the Department of Gastroenterological Surgery and the Pathological Diagnosis Database in the Department of Pathology. The Institutional Review Board of Toranomon Hospital approved the following
Molecular cancer, 2016
Colorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females. PD-1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment. However, the prognostic value of PD-1/PD-L1 in CRC remains unclear. The Cancer Genome Atlas (TCGA) database (N = 356) and Fudan University Shanghai Cancer Center (FUSCC) cohort of patients (N = 276) were adopted to analyze the prognostic value of PD-L1 in colorectal tumor cells (TCs) and of PD-1 in tumor infiltrating cells (TILs) for CRC. Subgroup analyses were conducted in FUSCC cohort according to patients' status of mismatch repair. In TCGA cohort, the cut-off values of PD-1 and PD-L1 expression were determined by X-tile program, which were 4.40 and 2.92, respectively. Kaplan-Meier analysis indicated that higher PD-1 and PD-L1 expressions correlated with better OS (P = 0.032 and P = 0.002, respectively). In FUSCC cohort, expressions of PD-1 on TILs and PD-L1 on TCs were analyzed s...
The Egyptian Journal of Hospital Medicine
Background: colorectal cancer (CRC) is a major cause of cancer-related death worldwide. In recent years, targeting the programed cell death (PD-1)/ programed cell death-1 ligand (PD-L1) immune checkpoint signaling has been tested as a novel promising treatment strategy in several tumors. Aim of the work: the present study aimed to examine expression of PD-L1 and CD 8+ T cells in CRC and to evaluate the relationship between their expressions and the different clinicopathological features. Material and methods: expression of PD-L1 in tumor cells (TC) as well as in tumor infiltrating immune cells (TIMC) was separately evaluated in 85 cases of CRC by the immunohistochemistry, in addition, CD8+ T cell count was assessed. Results: 12.9 % of cases showed PD-L1 expression in TC while, 28.2% showed PD-L1expression in TIMC. PD-L1 expression in TC was significantly associated with higher tumor grade (P =0.001), lymph node metastasis (LNM) (P =0.006) and lymphovascular invasion (LVI) (P > 0.001). On the other hand, PDL-1 expression in TIMC was significantly associated with low tumor grade (P=0.016), negative LVI (P = 0.004), high tumor infiltrating lymphocytes (TILs) count (P <0.0001), as well as high CD8+ T cells count (P = 0.002). High intra CD8-positive T cells was significantly associated with absence of LNM (P =0.013) and negative LVI (P =0.035). Conclusion: these findings indicated that expression of PD-L1 can be used as a new biomarker to predict the prognosis of colon cancer and may provide a clue for immunotherapy in the adjuvant treatment of CRC patients.
Programmed Cell Death-Ligand 1 (PD-L1) Expression in Anal Cancer
American Journal of Clinical Oncology, 2018
Background: This study was conducted to explore programmed cell deathligand-1 (PD-L1) expression and fibroblast growth factor receptor 1 (FGFR1) amplification in stage IIIB/IV lung squamous cell carcinoma (SQC). Correlations between PD-L1 and FGFR1, and with clinicopathological characteristics, efficacy of platinum-based chemotherapy, and prognosis were analyzed. Methods: One hundred and twenty-eight consecutive stage III/IV SQC patients were enrolled in this study from 2009 to 2014. Seventy-eight patients received platinum-based chemotherapy. Immunohistochemistry was used to assess PD-L1 expression and fluorescence in situ hybridization was applied to detect FGFR1 amplification. Results: PD-L1 expression was detected in 61.7% (79/128) of lung SQC patients. Smokers had significantly higher PD-L1 expression rates than non-smokers (66.1% vs. 44.0%, P = 0.042, respectively). The objective response and disease control rates for platinum-based chemotherapy were not significantly different between PD-L1 negative and positive patients (43.3% vs. 36.2%, P = 0.434; 80.0% vs. 78.7% P = 0.840, respectively); however, overall survival in PD-L1-negative patients was significantly longer than in PD-L1-positive patients (41.5 vs. 19.3 months, P = 0.001). Twenty-five percent (32/128) of patients displayed FGFR1 amplification, with a lower rate in stage III patients compared to stage IV (17.1% vs. 36.5%, P = 0.013, respectively). There was no significant difference in FGFR1 amplification levels between overall response, disease control or overall survival rates. No correlation was observed between PD-L1 expression and FGFR1 amplification (P = 0.916). Conclusion: PD-L1 expression may function as a prognostic factor in Chinese stage III/IV SQC patients. FGFR1 amplification is more prevalent in late stage SQC patients but does not predict chemotherapy response. There is no apparent correlation between PD-L1 expression and FGFR1 amplification.
Journal of laboratory physicians, 2023
Background Colorectal adenocarcinoma is the fourth leading cause of cancer-related mortality worldwide. These tumors are heterogeneous in terms of genomic alterations, immune response of the microenvironment, drug responsiveness, and biological behavior. Physiologically and pathologically, programmed cell death ligand 1 (PD-L1) is a key immune-regulatory molecule that suppresses immune response. PD-L1 expression on tumor cell has been implicated as a cause of immune evasion by tumor cells in many cancers. However, its activity in colorectal carcinomas is still under study. Objectives The aim of this study is to correlate PD-L1 marker expression with patient demographics, clinicopathological features, and TNM (tumor size, node involvement, and metastasis status) stage, and to find if there exists any significant correlation between them. Materials and Methods The present study is a 3-year retrospective analytical study conducted in a tertiary care hospital in South India. Specimens were routinely fixed, processed, and cut. Hematoxylin and eosin-stained sections and corresponding PD-L1stained sections were analyzed and data were tabulated. Statistical analysis Results were tabulated and statistical analysis was done using Statistical Package for the Social Sciences (SPSS) software (version 24). The chi-squared test was used to calculate the value of significance (p value). Results PD-L1 expression on tumor cells was significantly associated with female gender, right-sided tumors, poorly differentiated tumors, higher number of tumorinfiltrating lymphocytes, and higher T and N statuses. Conclusion High PD-L1 expression on tumor cells is a marker for poor prognosis. A subset of colorectal adenocarcinoma may benefit with anti-PD-L1-targeted therapy.
Colorectal carcinoma (CRC) is one of the most frequently encountered neoplasms with high morbidity and mortality. Activation of the programmed death protein 1/ programmed death ligand 1 (PD-1/PD-L1) pathway results in tumor immune evasion by suppressing the activity of T cells. The correlation of PD-L1 with clinicopathological features, lymph node metastasis and prognosis is less clear. The aim of present work was to study the relationship between PD-L1 and clinicopathological features and prognosis of CRC patients. Three hundred and eighty-six patients were included in this study. Serum PD-L1 was measured by ELISA, and PD-L1 on tumor cells was evaluated by immunohistochemistry. Pretreatment levels of PD-L1 were significantly elevated in CRC patient sera compared to healthy donors (P<0.001). The mean value of PD-L1 in healthy donors, CRC with non-lymph node metastasis, and CRC with lymph node metastasis were 229.22±54.7pg/mL, 400.77±66.3pg/ mL, and 414.29±59.1pg/mL, respectively. The positive rate of PD-L1 in metastatic lymph node was higher than in primary tumor (P<0.001). PD-L1 negative patients had higher five-year survival rate than PD-L1 positive patients (68.57% vs 46.98%, P=0.012). The univariate analysis indicated that tumor differentiation, lymph node metastasis, and PD-L1 were correlated with five-year survival rate of CRC patients (all P < 0.018). Multivariate analysis showed that lymph node metastasis and PD-L1 were independent prognostic factors (all P < 0.008). Our study demonstrates that PD-L1 negative patients have better five-year survival rate, and PD-L1 and lymph node metastasis are independent prognostic factors in CRC patients.