Programmed death-ligand 1 and survival in colorectal cancers: A meta-analysis

Abstract

Background:

Programmed death-ligand 1 (PD-L1) is a programmed death 1 (PD-1) ligand that plays a pivotal role in the inhibition of the T-cell-mediated immune response. The expression of PD-L1 is associated with the prognosis and clinical outcomes of multiple tumors. However, the prognostic value of PD-L1 overexpression in colorectal cancer is still controversial. In this study, we sought to clarify this by presenting a meta-analysis of relevant studies.

Methods:

Databases including PubMed, Web of Science, and EMBASE were systematically searched for studies concerning the expression of PD-L1 and survival in colorectal cancer. The reported hazard ratios (HR) with 95% confidence intervals (CI) of overall survival, disease-free survival, and recurrence-free survival in the included studies were analyzed by fixed effects/random effects models.

Results:

Fifteen studies involving 3078 patients with colorectal cancer were included in our meta-analysis. Overexpression of PD-L1 was found to be associated with poor overall survival (HR 1.83; 95% CI 1.21, 2.79; P = 0.005) and poor recurrence-free survival (HR 2.78; 95% CI 1.43, 5.42; P = 0.003). However, no correlation was found between PD-L1 overexpression and poor disease-free survival (HR 1.23; 95% CI 0.83, 1.82; P = 0.305). Overexpression of PD-L1 indicating poor survival held true across different geographical areas, sample sizes, analysis types, sources of HRs, and cell types.

Conclusion:

Overexpression of PD-L1 is associated with worse prognosis in patients with colorectal cancer and can guide physicians in the application of PD-1/PD-L1 immune checkpoint-targeted therapy.

Keywords

Programmed death-ligand 1 PD-L1 colorectal cancer prognosis survival

Introduction

Co-stimulatory and co-inhibitory receptors play a crucial role in T-cell biology because they determine the functional outcome of T-cell receptor signaling.^1,2 Antigen-dependent and antigen-independent signal transduction pathways participate in regulating classic T-cell activation.³ Programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 are two immune checkpoint molecules involved in cancer immunoediting, which suppress T-cell-mediated immune responses, leading to the development of cancers. Programmed death-ligand 1 (PD-L1, also known as B7-H1 and CD274), is a PD-1 ligand that plays a pivotal role in the inhibition of the T-cell-mediated immune response. The expression of this ligand is associated with prognosis and clinical outcomes of multiple tumors.^4-7

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide.^8,9 Considerable advances have been achieved in the treatment of CRC,¹⁰ but the 5-year survival rate remains poor,¹¹ and there is still some question regarding the independent predictors of poor CRC prognosis. Recently, researchers have begun to explore the prognostic value of PD-L1 overexpression in different solid tumors. Unlike its clear role in gastric cancer,^12-14 the prognostic value of PD-L1 overexpression in CRC is still controversial. Here we present a meta-analysis evaluating the prognostic value of PD-L1 overexpression in CRC. The purpose of this study was to estimate the correlation of PD-L1 with prognosis in CRC and to provide further direction for research into PD-1/PD-L1 immune checkpoint-targeted therapy and prognostic prediction.

Methods

Literature search strategies

PubMed, Web of Science, and EMBASE were searched for studies evaluating the expression of PD-L1 and survival in CRC. The search items included “CRC”, “colorectal cancer”, “colorectal tumor”, “colorectal neoplasms”, “colon cancer” or “rectal cancer”, “survival”, “prognostic”, “prognosis” or “outcome” and “PD-L1”, “Programmed death-ligand 1”, “cluster of differentiation 274”, “CD274”, “B7H1” or “B7 homolog 1”. All entries satisfying these criteria were manually retrieved.

Study inclusion and exclusion criteria

Eligible studies were included when meeting the following criteria: (a) the diagnosis of CRC was confirmed pathologically; (b) data on overall survival (OS), disease-free-survival (DFS), and recurrence-free survival (RFS) were available for evaluating the correlation of CRC prognosis with PD-L1 expression; and (c) hazard ratio (HR) and 95% confidence interval (CI) values were directly provided or could be calculated. Animal studies, reviews, editorials, comments, meetings, or case reports were excluded.

Data extraction

A standard protocol was adopted to extract data. The following data were extracted from each eligible study: (a) study characteristics including the first author, year of publication, country of origin, number of patients, duration of follow-up, and method of analysis; (b) patient characteristics including geographical area, age, gender, cell type, tumor stage, and cut-off value; and (c) statistical data including HRs of OS, DFS, and RFS and their 95% CIs. The HRs were extracted directly from univariate and multivariate analyses or calculated from Kaplan–Meier survival curves.¹⁵ This investigation was approved by the institutional ethics committee of the Third Affiliated Hospital of Soochow University.

Quality assessment

The Newcastle-Ottawa Scale¹⁶ was used for assessing the quality of each included study. The study was considered to be of high quality when the score was more than 6.

Statistical analysis

Data were extracted from the primary studies and analyzed using the Stata 12 Edition (Stata, College Station, TX, USA). Statistical heterogeneity was examined using the chi-square-based Q-test, in which the I² value indicates the degree of heterogeneity. A random-effects model (DerSimonian-Laird method) was applied in cases of significant heterogeneity (I² ⩾ 50% and P < 0.1), while a fixed-effects model (Mantel–Haenszel method) was used in the absence of heterogeneity. Subgroup analyses were conducted based on geographical area, sample size, analysis type, source of HR, and cell type. Sensitivity analyses were carried out to investigate the robustness of the findings. Publication bias was estimated by funnel plot and Egger’s linear regression test. All statistical tests in the meta-analysis were two-tailed and a P value ⩽ 0.05 was considered statistically significant.

Results

Search results

The systematic database search retrieved 955 articles. Each of these articles was carefully read and 940 articles were excluded from further analysis according to the inclusion criteria. The search results are shown in Figure 1. Based on the inclusion criteria, 15 articles were finally eligible for the meta-analysis.^17-31 A total of 3078 patients from China, South Korea, USA, Japan, Switzerland, and Germany were enrolled. Sample sizes of the studies ranged from 60 to 456 cases.

Figure 1.

Flow chart of the study selection process. The systematic database search retrieved 955 articles. Based on the inclusion criteria, 15 articles were eventually selected for the meta-analysis.

The characteristics of all included studies are shown in Table 1. Among the included articles, there were 21 sets of data in total examining the association between PD-L1 expression and prognosis, including 8 sets that analyzed OS, 7 DFS, and 6 RFS. Among all 15 eligible articles, 8 studies were from China, 3 from the USA, 2 from Japan, 1 from Korea, and 1 from Germany.

Table 1.

Major characteristics of the included studies.

Author	Year	Country	Area	Case number	Age	Gender(M/F)	Cell type	Tumorstage	Follow-up (months)	Cut-off Value	Survivalanalysis	Analysis	HR
Lee et al.¹⁷	2018	Korea	Eastern	89	Median 73	58/31	TIICs	Ⅰ-Ⅲ	Median 39	0	DFS	MV	Report
Liu et al.¹⁸	2018	China	Eastern	60	> 60	43/17	TIICs	NA	NA	0	OS	MV	Report
Li et al.¹⁹	2016	China	Eastern	276	Median 57	166/110	TCs	Ⅰ-Ⅳ	Median 61	2.92	OS/DFS	MV	Report
Lee et al.²⁰	2016	USA	Western	395	Mean 55	201/194	TCs	Ⅰ-Ⅳ	Mean 55	CS	RFS	MV	Report
Koganemaru et al.²¹	2017	Japan	Eastern	235	Median 63	140/95	TCs/TIICs	Ⅲ	Median 52.9	5%	DFS	MV	Report
Shao et al.²²	2017	China	Eastern	68	Median 53.5	46/22	TCs	Ⅱ-Ⅲ	Median 32.5	10%	DFS	UV	Report
Wang et al.²³	2018	China	Eastern	254	Median 56	160/94	TIICs	Ⅱ-Ⅲ	Mean 42	0	RFS	MV	Report
Wang et al.²⁴	2016	China	Eastern	262	Median 56.5	166/96	TCs/TIICs	Ⅱ-Ⅲ	Mean 43.5	0	RFS	MV	Report
Satelli et al.²⁵	2016	USA	Western	62	NA	NA	TCs	NA	NA	0	OS	NA	Report
Saigusa et al.²⁶	2016	Japan	Eastern	90	Median 64	64/26	TIICs	Ⅰ-Ⅳ	Median 46	CS	OS/RFS	MV	Report
Liang et al.²⁷	2014	China	Eastern	185	114/71 (⩾60/<60)	87/98	NA	Ⅰ-Ⅳ	NA	CS	OS/DFS/ RFS	NA	Report
Goltz et al.²⁸	2017	Germany	Western	383	Median 66	206/168	NA	Ⅰ-Ⅳ	Median 13.7	0	OS	MV	Report
Shi et al.²⁹	2013	China	Eastern	143	Mean 59.8	61/82	NA	Ⅰ-Ⅳ	NA	0	OS	MV	Report
Narayanan et al.³⁰	2018	USA	Western	456	Mean 67.3	240/216	TIICs	Ⅰ-Ⅳ	NA	CS	DFS	UV	SC
Zhu et al.³¹	2015	China	Eastern	120	Mean 67	71/49	TCs	Ⅰ-Ⅳ	Median 39	CS	OS	UV	SC

DFS: disease-free-survival; HR: hazard ratio; MV: multivariate analysis; NA: not available; OS: overall survival; RFS: recurrence-free survival; SC: survival curve; UV: univariate analysis.

Meta-analysis

Overall survival

Data on OS were collected from 1319 patients with CRC. Overexpression of PD-L1 was found to be associated with poor OS (HR 1.83; 95% CI 1.21, 2.79; P = 0.005). Significant heterogeneity was observed in these studies (P = 0.004; I² = 66.7%; Figure 2(a)).

Figure 2.

Forest plots of studies evaluating the HR of programmed death-ligand 1 (PD-L1) in patients with CRC. (a) Overexpression of PD-L1 was found to be associated with poor OS (HR 1.83; 95% CI 1.21, 2.79; P = 0.005). (b) No correlation was found between PD-L1 overexpression and poor DFS (HR 1.23; 95% CI 0.83, 1.82; P = 0.305). (c) Overexpression of PD-L1 was found to be associated with poor RFS (HR 2.78; 95% CI 1.43, 5.42; P = 0.003).

Disease-free-survival

Data on DFS were provided by 1309 patients with CRC and indicated no correlation between PD-L1 overexpression and poor DFS (HR 1.23; 95% CI 0.83, 1.82; P = 0.305). Significant heterogeneity was observed in these studies (P = 0.002; I² = 71.6%; Figure 2(b)).

Recurrence-free survival

Data on RFS were extracted from 1186 CRC patients and indicated a correlation between PD-L1 overexpression and poor RFS (HR 2.78; 95% CI 1.43, 5.42; P = 0.003). Significant heterogeneity was observed in these studies as well (P = 0.010; I² = 66.8%; Figure 2(c)).

Subgroup analysis

Subgroup analysis was performed based on geographical area, sample size, analysis type, source of HRs, and cell type. Heterogeneity occurred in each subgroup (Table 2).

Table 2.

Subgroup analyses based on different categories.

Variables	Outcome	Studies	HR (95% CI)	P Value	Model	Heterogeneity
Variables	Outcome	Studies	HR (95% CI)	P Value	Model	I²	P
ALL	OS	8	1.83 (1.21, 2.79)	0.005	random	66.7	0.004
	DFS	7	1.23 (0.83, 1.82)	0.305	random	71.6	0.002
	RFS	6	2.78 (1.43, 5.42)	0.003	random	66.8	0.010
Area
Eastern	OS	6	1.65 (1.05, 2.60)	0.03	random	71.2	0.004
	DFS	6	1.17 (0.66, 2.07)	0.592	random	76.2	0.001
	RFS	5	2.35 (1.26, 4.36)	0.007	random	64.6	0.024
Western	OS	2	4.44 (0.74, 26.47)	0.102	random	52.3	0.148
	DFS	1	1.35 (1.09, 1.67)	–	–	–	–
	RFS	1	22.86 (1.99, 263.21)	–	–	–	–
Sample size
> 200	OS	2	3.22 (0.21, 48.37)	0.398	random	77.8	0.034
	DFS	4	1.20 (0.78, 1.85)	0.416	random	67.2	0.027
	RFS	4	1.81 (1.27, 2.58)	0.001	fixed	36.1	0.196
⩽ 200	OS	6	1.98 (1.30, 2.96)	0.001	random	59.0	0.032
	DFS	3	1.22 (0.39, 3.78)	0.731	random	82.2	0.004
	RFS	2	12.93 (0.48, 351.15)	0.129	random	85.3	0.009
Analysis type
Univariate	OS	1	2.47 (1.44, 4.23)	–	–	–	–
	DFS	2	1.39 (1.12, 1.71)	0.002	fixed	42.8	0.188
Multivariate	OS	5	1.39 (0.78, 2.48)	0.263	random	84.0	< 0.001
	DFS	4	0.85 (0.39, 1.82)	0.669	random	77.3	0.004
	RFS	5	1.92 (1.38, 2.67)	< 0.001	fixed	27.6	0.237
NA	OS	2	1.87 (1.30, 2.69)	0.001	fixed	0	0.457
	DFS	1	1.83 (1.21, 2.81)	–	–	–	–
	RFS	1	84.7 (7.85, 915)	–	–	–	–
HR obtain method
Reported in text	OS	7	1.73 (1.06, 2.82)	0.028	random	69.4	0.003
	DFS	6	1.17 (0.66, 2.07)	0.592	random	76.2	0.001
	RFS	6	2.78 (1.43, 5.42)	0.003	random	66.8	0.010
Data-extrapolated	OS	1	2.47 (1.44, 4.23)	–	–	–	–
	DFS	1	1.35 (1.09, 1.67)	–	–	–	–
Cell type
TCs	OS	3	1.79 (0.97, 3.29)	0.062	random	68.4	0.042
	DFS	3	1.70 (0.76, 3.80)	0.195	random	74.3	0.02
	RFS	2	4.98 (0.46, 53.50)	0.185	random	72.4	0.057
TIICs	OS	2	0.87 (0.10, 7.40)	0.901	random	87.6	0.004
	DFS	3	0.69 (0.27, 1.76)	0.433	random	80.8	0.005
	RFS	3	1.81 (1.25, 2.63)	0.002	fixed	0	0.475
NA	OS	3	2.40 (1.32, 4.36)	0.004	random	55.7	0.105
	DFS	1	1.74 (1.20, 2.71)	–	–	–	–
	RFS	1	1.74 (1.20, 2.71)	–	–	–	–

CI: confidence interval; DFS: disease-free survival; HR: hazard ratio; NA: not available; OS: overall survival; RFS: recurrence-free survival; TCs: tumor cells; TIICs: tumor infiltrating immune cells.

Sensitivity analysis

Sensitivity analysis was performed for OS (Figure 3(a)), DFS (Figure 3(b)), and RFS (Figure 3(c)) through the sequential omission of each study. As a result, no single study was able to change the overall results, which demonstrated the robustness of the results in our meta-analysis.

Figure 3.

Sensitivity analyses confirming the robustness of OS (a), DFS (b), and RFS (c) through the sequential omission of each study. No single study was able to change the overall results, which demonstrated the stability of the results in our meta-analysis.

Publication bias

The publication bias of all enrolled studies was evaluated using funnel plots and Egger’s linear regression test. The results showed no significant publication bias in OS (P = 0.863, Supplementary material 1(a)) and DFS (P = 0.649, Supplementary material 1(b)). However, visual inspection of the funnel plot (Supplementary material 1(c)) revealed evidence of publication bias for RFS, which was confirmed by Egger’s tests (P = 0.009). Using the “Trim and Fill” method to adjust for publication bias under the random-effects model, the corrected pooled multivariable-adjusted HR for RFS was 1.67 (95% CI 1.25, 2.11).

Discussion

PD-L1 is primarily expressed on the surface of tumor cells (TCs) and other tumor-promoting cells in various solid tumors, including melanoma,^32,33 colorectal cancer,²⁹ lung cancer,^34-36 pancreatic carcinoma,³⁷ and hepatocellular carcinoma.³⁸ The PD-1/PD-L1 pathway plays an important role in immune regulation. Blocking the interaction between PD-1 and PD-L1 has been shown to exert an antitumor effect.³⁹ Therapeutics targeting the PD-1/PD-L1 pathway are currently undergoing clinical trials, and recent clinical trials have demonstrated that multiple cancer patients can achieve benefit from immune check-point targeted therapy.⁴⁰ However, the prognostic value of PD-L1 overexpression in CRC patients has not been fully addressed to date. This meta-analysis was designed to investigate the relationship between the PD-L1 overexpression and prognosis in 15 studies involving 3078 patients with CRC. The results showed that overexpression of PD-L1 was associated with worse OS and RFS. No relationship was found between PD-L1 overexpression and DFS. Furthermore, subgroup analysis revealed that overexpression of PD-L1 was associated with poor survival, but no significant difference was found among different subgroups, which was consistent with the results derived from the overall analysis.

Some studies have reported that PD-L1 overexpression was associated with worse 5-year survival of patients with digestive tract-derived cancers including esophageal cancer,⁴¹ gastric cancer,⁴² and colorectal cancer,^29,43 which is consistent with our results. Similar conclusions were drawn in two other studies,^26,27 showing that PD-L1 overexpression was an independent predictor of poor CRC survival. Although we found no relationship between PD-L1 overexpression and DFS in this meta-analysis, on the whole our analyses revealed that PD-L1 overexpression was associated with poor prognosis.

Despite a host of studies supporting our results, there have been some differing observations. The status of DNA mismatch repair (MMR) described as MMR-proficient or MMR-deficient was also reported to be significant in predicting prognosis upon PD-L1 expression on TCs.⁴⁴ Droeser et al.⁴⁴ concluded that PD-L1 expression was associated with better survival in MMR-proficient CRCs, which may have resulted from the increase in infiltrating CD8⁺ T cells. Another study illustrated that PD-L1 expression in tumor-infiltrating immune cells (TIICs) was associated with a better prognosis for patients with microsatellite instability-high (MSI-H) colon cancer.¹⁷ MSI-H is a hypermutable phenotype caused by impaired DNA MMR. A similar conclusion was drawn by Ogino et al.,⁴⁵ who found that MSI-H tumors have a better prognosis than microsatellite-stable CRCs. In our opinion, the correlation of MMR-proficient and MSI-H phenotypes with better prognosis in CRC requires further research and exploration.

As is well known, PD-L1 is not only expressed in TCs, but also upregulated in TIICs.³ Where PD-L1 is expressed may produce different findings. Although previous studies have confirmed that high expression of PD-L1 on TCs was linked with worse survival in CRC patients,^22,31 only a few studies have examined the association between PD-L1 expression on TIICs and prognosis in CRC patients. Recently, two studies revealed that high PD-L1 expression on TIICs was associated with a favorable prognosis in CRC patients.^17,21 Different mechanisms regulating PD-L1 expression on TCs and TIICs may explain these different results. PD-L1 expression on TIICs was found to play a role in tumor immune escape and to affect tumor progression, which accounted for its relationship with a favorable prognosis.⁴⁶

Although we performed an exhaustive meta-analysis, some limitations to our conclusions should be noted. First, the sample size was relatively small. Second, we calculated HRs and 95% CIs from Kaplan–Meier survival curves, which may have contained errors compared to direct data from the original studies. Third, we generally covered stage I-IV CRC patients and we did not perform subgroup analysis based on CRC stage. A study concerning PD-L1 and each CRC stage is warranted in the future to explore whether the role of PD-L1 changes according to the stage of CRC. Finally, despite the application of the random-effects model, subgroup analysis and sensitivity analysis, there was still substantial heterogeneity in some of the subgroups.

Conclusion

In summary, this meta-analysis revealed that overexpression of PD-L1 was associated with worse prognosis in patients with CRC, which suggests that the development of PD-L1/PD-1 immune checkpoint-targeted therapy may be a promising approach, which will offer more options for the treatment of patients with CRC.

Supplemental Material

Supplementary_material_1 – Supplemental material for Programmed death-ligand 1 and survival in colorectal cancers: A meta-analysis

Supplemental material, Supplementary_material_1 for Programmed death-ligand 1 and survival in colorectal cancers: A meta-analysis by Huihua Cao, Qing Wang, Zhenyan Gao, Zhan Yu, Yugang Wu and Qicheng Lu in The International Journal of Biological Markers

Supplemental Material

Supplementary_material_2 – Supplemental material for Programmed death-ligand 1 and survival in colorectal cancers: A meta-analysis

Supplemental material, Supplementary_material_2 for Programmed death-ligand 1 and survival in colorectal cancers: A meta-analysis by Huihua Cao, Qing Wang, Zhenyan Gao, Zhan Yu, Yugang Wu and Qicheng Lu in The International Journal of Biological Markers

Footnotes

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University.

Author contributions

HC and QW wrote the manuscript, analyzed collected data, and contributed equally to this study. ZG and ZY carried out the database search and collected data. YW and QL assisted HC and QW to complete the work. YW funded the study.

Declaration of conflicting interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The present study was supported by the Changzhou Municipal Scientific Research grant (grant no. CE20125020).

ORCID iD

Yugang Wu

Supplemental material

Supplemental material for this article is available online.

References

, et al. PD-L1 and survival in solid tumors: A meta-analysis. PLoS One 2015; 10: e0131403.

Chen

Flies

DB.

Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013; 13: 227–242.

Wang

Teng

Kong

, et al. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther 2016; 9: 5023–5039.

Brahmer

Drake

Wollner

, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28: 3167–3175.

Brahmer

Tykodi

Chow

, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455–2465.

Hamid

Robert

Daud

, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369: 134–144.

Topalian

Sznol

McDermott

, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32: 1020–1030.

Huang

, et al. CD133 expression correlates with clinicopathologic features and poor prognosis of colorectal cancer patients: An updated meta-analysis of 37 studies. Medicine 2018; 97: e10446.

Passardi

Canale

Valgiusti

, et al. Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci 2017; 18: E1324.

10.

Chen

, et al. Prognostic value of pretreatment serum carbohydrate antigen 19–9 level in patients with colorectal cancer: A meta-analysis. PLoS One 2017; 12: e0188139.

11.

Oliphant

Nicholson

Horgan

, et al. Deprivation and colorectal cancer surgery: longer-term survival inequalities are due to differential postoperative mortality between socioeconomic groups. Ann Surg Oncol 2013; 20: 2132–2139.

12.

Hou

Xiang

, et al. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Mol Pathol 2014; 96: 284–291.

13.

Zhu

Jiang

, et al. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006; 108: 19–24.

14.

Qing

Ren

, et al. Upregulation of PD–L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther 2015; 9: 901–909.

15.

Parmar

Torri

Stewart

Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17: 2815–2834.

16.

Stang

Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603–605.

17.

Lee

Jun

Lee

, et al. CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. J Cancer Res Clin Oncol 2018; 144: 1005–1014.

18.

Liu

Peng

, et al. Prognostic value of immunoscore and PD-L1 expression in metastatic colorectal cancer patients with different RAS status after palliative operation. Biomed Res Int 2018; 2018: 5920608.

19.

Liang

Dai

, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer 2016; 15: 55.

20.

Lee

Cavalcanti

Segal

, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol 2016; 29: 1433–1442.

21.

Koganemaru

Inoshita

Miura

, et al. Prognostic value of programmed death-ligand 1 expression in patients with stage III colorectal cancer. Cancer Sci 2017; 108: 853–858.

22.

Shao

Peng

, et al. Tumor cell PD-L1 predicts poor local control for rectal cancer patients following neoadjuvant radiotherapy. Cancer Manag Res 2017; 9: 249–258.

23.

Wang

Liu

Fisher

, et al. Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer. Hum Pathol 2018; 71: 20–29.

24.

Wang

Ren

Wang

, et al. Significance of programmed death ligand 1 (PD-L1) immunohistochemical expression in colorectal cancer. Mol Diagn Ther 2016; 20: 175–181.

25.

Satelli

Batth

Brownlee

, et al. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci Rep 2016; 6: 28910.

26.

Saigusa

Toiyama

Tanaka

, et al. Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol 2016; 21: 946–952.

27.

Liang

Wang

, et al. T-cell infiltration and expressions of T lymphocyte co-inhibitory B7-H1 and B7-H4 molecules among colorectal cancer patients in northeast China’s Heilongjiang province. Tumour Biol 2014; 35: 55–60.

28.

Goltz

Gevensleben

Dietrich

, et al. PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients. Oncoimmunology 2017; 6: e1257454.

29.

Shi

Wang

, et al. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One 2013; 8: e76012.

30.

Narayanan

Kawaguchi

Yan

, et al. Cytolytic activity score to assess anticancer immunity in colorectal cancer. Ann Surg Oncol 2018; 25: 2323–2331.

31.

Zhu

Qin

Huang

, et al. Clinical significance of programmed death ligand-1 (PD-L1) in colorectal serrated adenocarcinoma. Int J Clin Exp Pathol 2015; 8: 9351–9359.

32.

Hino

Kabashima

Kato

, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010; 116: 1757–1766.

33.

Taube

Anders

Young

, et al. Colocalization of inflammatory response with B7–h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012; 4: 127ra37.

34.

Konishi

Yamazaki

Azuma

, et al. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 2004; 10: 5094–5100.

35.

Huang

Chen

, et al. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 2011; 28: 682–688.

36.

Yang

Lin

Chang

, et al. Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer 2014; 50: 1361–1369.

37.

Chen

Yuan

Chen

, et al. Expression of B7-H1 protein in human pancreatic carcinoma tissues and its clinical significance. Ai Zheng 2009; 28: 1328–1332.

38.

Gao

Wang

Qiu

, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009; 15: 971–979.

39.

Mahoney

Freeman

McDermott

DF.

The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther 2015; 37 (4): 764–82.

40.

Page

Postow

Callahan

, et al. Immune modulation in cancer with antibodies. Ann Rev Med 2014; 65: 185–202.

41.

Chen

Deng

, et al. B7–H1 expression associates with tumor invasion and predicts patient’s survival in human esophageal cancer. Int J Clin Exp Pathol 2014; 7: 6015–6023.

42.

Geng

Wang

, et al. Expression of costimulatory molecules B7–H1, B7–H4 and Foxp3+ Tregs in gastric cancer and its clinical significance. Int J Clin Oncol 2015; 20: 273–281.

43.

Zhu

Chen

Zou

, et al. MiR-20b, -21, and -130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer. Hum Immunol 2014; 75: 348–353.

44.

Droeser

Hirt

Viehl

, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 2013; 49: 2233–2242.

45.

Ogino

Nosho

Kirkner

, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 2009; 58: 90–96.

46.

Yang

Lin

Chang

, et al. Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma. Eur J Cancer 2016; 57: 91–103.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.30 MB

0.32 MB