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. 2017 Dec 22;9(4):5058–5072. doi: 10.18632/oncotarget.23580

Prognostic value of PD –L1 expression in patients with primary solid tumors

Xiao Xiang 1, Peng-Cheng Yu 2, Di Long 2, Xiao-Li Liao 1, Sen Zhang 2, Xue-Mei You 1, Jian-Hong Zhong 1, Le-Qun Li 1
PMCID: PMC5797033  PMID: 29435162

Abstract

Programmed death-ligand 1 (PD-L1) is thought to play a critical role in immune escape by cancer, but whether PD-L1 expression can influence prognosis of patients with solid tumors is controversial. Therefore, we meta-analyzed available data on whether PD-L1 expression correlates with overall survival (OS) in such patients. PubMed, EMBASE and other databases were systematically searched for cohort or case-control studies examining the possible correlation between PD-L1 expression and OS of patients with solid tumors. OS was compared between patients positive or negative for PD-L1 expression using scatter plots, and subgroup analyses were performed based on tumor type and patient characteristics. Data from 59 studies involving 20,004 patients with solid tumors were meta-analyzed. The median percentage of tumors positive for PD-L1 was 30.1%. OS was significantly lower in PD-L1-positive patients than in PD-L1-negative patients at 1 year (P = 0.039), 3 years (P < 0.001) and 5 years (P < 0.001). The risk ratios of OS (and associated 95% confidence intervals) were 2.02 (1.56-2.60) at 1 year, 1.57 (1.34-1.83) at 3 years and 1.43 (1.24-1.64) at 5 years. Similar results were obtained in subgroup analyses based on patient ethnicity or tumor type. The available evidence suggests that PD-L1 expression negatively affects the prognosis of patients with solid tumors. PD-L1 might serve as an efficient prognostic indicator in solid tumor and may represent the important new therapeutic target.

Keywords: primary solid tumors, programmed death ligand 1, overall survival, meta-analysis

INTRODUCTION

Immune co-stimulatory and co-inhibitory receptors determined the functional outcome of T cell receptor (TCR) signaling and immune surveillance [1]. Tumors can modulate the interactions between inhibitory receptors and ligands to scape immune responses [2, 3]. For example, the co-inhibitory receptor programmed cell death 1 (PD-1) plays a key role in cancer immune, especially in the immune escape phase [4]. PD-1 can be expressed in activated CD4 + and CD8 + T cells, but also in some natural killer cells and B cells [5]. When PD-1 binds to the ligand PD-L1 (B7-H1) expressed on the surface of tumors, it strongly inhibits the production of T cells and cytokines [6, 7], promoting tumor cell growth and immune escape [8, 9].

PD-L1 also plays a key role in binding to PD-1 receptors expressed on activated T cells in T cell co-suppression and depletion [9–11]. PD-L1 expressed on tumor cells promotes tumor cell-specific T cell inactivation or apoptosis, leading to tumor cell growth and exacerbation of tumor immune escape [12]. PD-L1 is expressed in many types of human cancers, including in esophageal, gastrointestinal, pancreatic, breast, lung and kidney cancers [10–14]. Clinical trials suggest that blocking the PD-1/PD-L1 interaction using anti-PD-1 antibodies can be effective against several different malignancies, including melanoma, lung cancer, kidney cancer and bladder cancer [15–19].

In addition to serving as a therapeutic target, PD-L1 may also be useful as a prognostic biomarker [22]. However, whether PD-L1 expression is associated with worse prognosis for patients with primary solid tumors remains controversial [20–22]. Therefore we meta-analyzed all available evidence to address this question comprehensively.

RESULTS

A total of 1,258 records were retrieved from PUBMED, EMBASE, Web of Science and EBSCO (Figure 1). After excluding 825 duplicate publications, we reviewed the abstracts and titles of the remaining 433 articles. This led to the exclusion of another 288 records that were not original research articles published in English. The remaining articles were read in full, leading to the exclusion of 86 records because they did not deal with human patients or solid tumors, or because they failed to report adequate outcomes data. In the end, 59 articles were included in the meta-analysis.

Figure 1. Flow chart of study selection.

Figure 1

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Key features of the 59 studies are summarized in Table 1; 35 studies involved Asian populations and 24 involved non-Asian populations. The studies analyzed 20,004 patients from China [23–41], France [42], New Zealand [43, 44], Brazil [45], Australia [46], Canada [47, 48], Italy [49], Germany [50, 51], United States [52–65], Japan [66–74], South Korea [75–78], Switzerland [79] and Taiwan [80, 81]. PD-L1 expression, which was analyzed in similar ways across all studies, was characterized as positive in 6,028 patients and negative in the remaining 13,976. One third of the studies (19) involved gastrointestinal tumors, while the remaining 40 involved other types of tumors. Altogether 11 malignancies were represented in the patient population: breast cancer (5 studies), renal cell carcinoma (7), colorectal cancer (3), esophageal cancer (3), gastric cancer (7), hepatocellular carcinoma (7), Merkel cell carcinoma (3), small cell lung cancer (11), oral squamous cell carcinoma (5), pancreatic cancer (3), and urinary tract epithelial cell carcinoma (4).

Table 1. Characteristics of studies included in the meta-analysis.

Study Country Tumor type Characteristic Age Gender
male / female		 No. patients positive/ negative for PD-L1 PD-L1-positive OS (%) PD-L1-negative OS (%) P
1-yr 3-yr 5-yr 1-yr 3-yr 5-yr
Qin 2015 China Breast cancer Primary 47(21-84) - 189/681 100 85 81 100 98 92 <0.001
Sabatier 2015 France Breast cancer Primary ≤50: 1288
1021 (28%)
267 (31%)
>50: 3207		 - 1076/4378 97 90 82 97 90 81 0.070
Muenst 2014 Switzerland Breast cancer Primary 63.8 ± 14.2 - 152/498 90 55 37 98 85 80 <0.001
Baptista 2016 Brazil Breast cancer Primary ≤50: 176
1021 (28%)
267 (31%)
>50: 204		 107/82 98 90 85 100 96 93 0.030
Beckers 2016 Australia Breast cancer Primary - - 123/38 96 92 81 96 73 65 0.035
Droeser 2013 Italy Colorectal cancer Primary 69.9 (30–96) 741/673 669/1420 84 71 61 72 48 37 <0.001
Shi SJ 2013 China Colorectal cancer Primary 59.8 ± 12.5 91/116 64/143 75 54 42 90 72 61 0.017
Zhu 2014 China Colorectal cancer Primary ≤50: 54
1021 (28%)
267 (31%)
>50: 47		 53/48 55/46 - - 62 - - 80 0.051
Krambeck 2007 USA Renal cell carcinoma Primary ≤65: 54
1021 (28%)
267 (31%)
>65: 47		 150/148 70/228 78 62 48 91 83 76 <0.005
Thompson 2005 Canada Renal cell carcinoma Primary - - 103/196 84 67 52 93 87 84 <0.001
Thompson 2007 Canada Renal cell carcinoma Primary ≤65: 138
1021 (28%)
267 (31%)
>65: 129		 177/90 142/267 88 68 - 94 85 - 0.004
Abbas 2016 Germany Renal cell carcinoma Primary 63 (31–88) 116/61 37/140 85 57 47 92 75 66 0.005
Choueiri 2014 USA Renal cell carcinoma Primary 59 (24–81) 55/46 11/90 72 48 48 98 95 85 <0.001
Thompson 2004 USA Renal cell carcinoma Primary - - 87/109 87 62 - 95 92 - <0.001
Thompson 2006 USA Renal cell carcinoma Primary - - 73/233 78 51 42 95 90 83 <0.001
Ohigashi 2005 Japan Esophageal cancer Primary ≤65: 24
1021 (28%)
267 (31%)
>65: 17		 32/9 18/41 60 18 18 88 53 45 0.001
Tanaka 2016 Japan Esophageal cancer Primary 62.6 ± 10.0 157/33 53/127 61 30 25 79 56 51 0.001
Chen 2014 China Esophageal cancer Primary ≤65: 51
1021 (28%)
267 (31%)
>65: 48		 76/23 79/20 100 44 17 83 44 37 0.675
Loos 2011 Germany Esophageal cancer Primary - - 37/64 79 51 32 96 82 69 <0.001
Shohei 2016 Japan Gastric carcinoma Primary 67 ± 14 75/30 28/105 84 41 10 91 63 51 0.022
Geng 2015 China Gastric carcinoma Primary ≤65: 65
1021 (28%)
267 (31%)
>65: 35		 61/39 65/100 72 41 29 87 61 37 0.026
Hou 2014 China Gastric carcinoma Primary ≤58: 55
1021 (28%)
267 (31%)
>58: 56		 75/36 70/111 78 46 32 93 77 68 <0.001
Wu 2006 Sweden Gastric carcinoma Primary ≤65: 64
1021 (28%)
267 (31%)
>65: 38		 75/27 43/102 75 38 30 98 71 64 0.001
Tamura 2015 Japan Gastric carcinoma Primary 66.1 (17-89) 305/126 128/303 90 65 49 94 78 64 0.001
Zheng 2014 China Gastric carcinoma Primary ≤60: 42
1021 (28%)
267 (31%)
>60: 38		 62/18 33/47 86 65 52 91 69 53 0.636
Qing 2015 USA Gastric carcinoma Primary ≤60: 42
1021 (28%)
267 (31%)
>60: 38		 72/35 54/107 81 28 18 93 47 27 0.004
Gao 2009 China Hepatocellular carcinoma Primary 52 (18-81) 204/36 60/180 70 42 39 83 57 49 0.029
Jung 2016 South Korea Hepatocellular carcinoma Primary ≤53: 44
1021 (28%)
267 (31%)
>53: 41		 69/16 23/62 43 19 17 90 69 59 <0.001
Kan 2015 China Hepatocellular carcinoma Primary ≤50: 56
1021 (28%)
267 (31%)
>50: 72		 108/20 105/23 30 5 0 50 15 10 0.001
Umemoto 2015 Japan Hepatocellular carcinoma Primary 64 ± 10 71/9 37/43 74 51 40 80 73 71 0.051
Zeng 2011 China Hepatocellular carcinoma Primary 53.1(35–68 109/32 31/32 38 - - 85 - - 0.000
Gabrielson 2016 USA Hepatocellular carcinoma Primary 61 (30–86) 50/15 30/35 85 85 - 53 45 - 0.029
Wu 2009 China Hepatocellular carcinoma Primary 48, 23–75 65/6 35/36 81 54 40 97 83 71 0.014
Azuma 2014 Japan Lung cancer Primary 66 (39-82) 91/73 82/164 - - 38 - - 56 0.039
Chen 2012 China Lung cancer Primary ≤54: 23
1021 (28%)
267 (31%)
>54: 17		 26/14 69/120 71 11 - 85 48 - <0.001
Cooper 2015 USA Lung cancer Primary - 477/201 628/678 95 73 62 84 54 44 0.023
Jiang 2015 China Lung cancer Primary ≤60: 15
1021 (28%)
267 (31%)
>60: 64		 39/40 50/79 100 91 84 83 74 70 0.042
Kim 2015 South Korea Lung cancer Primary 65 (45–81) 33/8 89/331 65 38 27 78 49 49 0.570
Mu 2011 China Lung cancer Primary - - 58/109 87 20 - 95 38 - <0.005
Velcheti 2014 USA Lung cancer Primary ≤70: 232
1021 (28%)
267 (31%)
>70: 80		 260/37 56/155 78 43 27 87 61 51 0.028
Yang 2014 Taiwan Lung cancer Primary ≤70: 132
1021 (28%)
267 (31%)
>70: 31		 54/109 65/163 98 93 91 98 87 83 0.027
Zhang 2014 China Lung cancer Primary ≤58: 73
1021 (28%)
267 (31%)
>58: 70		 84/59 70/143 84 71 53 97 89 77 0.002
Song 2016 China Lung cancer Primary <60: 207
≥60: 178		 198/187 186/199 99 71 40 99 79 52 0.069
Inamura 2016 Japan Lung cancer Primary <60: 96
≥60: 172		 142/126 43/225 85 69 55 95 81 71 0.019
Chen 2009 China Pancreatic cancer Primary <60: 61
≥60: 55		 76/23 18/40 32 8 - 84 58 17 0.001
Nomi 2007 Japan Pancreatic cancer Primary - - 20/51 48 12 - 78 24 - 0.016
Wang 2010 China Pancreatic cancer Primary - 40/10 23/40 87 8 - 100 33 - <0.001
Gadiot 2011 Netherlands Merkel cell carcinoma Primary - 36/27 16/63 - 51 37 - 68 52 0.200
Hino 2010 Japan Merkel cell carcinoma Primary 68.84 ± 2.85 38/21 34/59 - - 52 - - 81 0.040
Taube 2012 USA Merkel cell carcinoma Primary - 76/74 57/150 - - 84 - - 61 0.330
Boorjian 2008 USA Urinary tract epithelial cell carcinoma Primary - 259/59 39/314 58 51 43 91 82 67 0.005
Nakanishi 2006 Japan Urinary tract epithelial cell carcinoma Primary - 47/18 46/65 86 68 57 100 100 100 0.021
Wang 2009 China Urinary tract epithelial cell carcinoma Primary - 31/5 36/50 91 68 - 100 100 - 0.020
Xylinas 2014 USA Urinary tract epithelial cell carcinoma Primary 65.9 (60.5e72.2) 244/58 76/226 83 66 63 95 82 69 0.020
Kim 2016 South Korea Oral squamous cell cancer Primary 65 (45–81) 33/8 90/43 97 83 80 98 83 75 0.625
Lin 2015 Taiwan Oral squamous cell cancer Primary <56: 162
≥56: 143		 236/69 133/172 81 62 56 81 62 58 0.225
Cho 2011 South Korea Oral squamous cell cancer Primary <59: 20
≥59: 25		 32/13 26/45 72 51 43 72 63 63 0.012
Oliveira 2015 USA Oral squamous cell cancer Primary <60: 62
≥60: 34		 85/11 47/96 81 47 - 61 18 - 0.044
Ukpo 2013 USA Oral squamous cell cancer Primary 55.8 ± 9.4 186/23 84/181 89 74 62 97 76 64 0.730
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PD-L1 expression and OS across all studies

Meta-analysis of data from all 59 studies showed that the median OS rate was significantly lower in PD-L1-positive patients than in PD-L1-negative patients at 1 year (P = 0.039), 3 years (P < 0.001) and 5 years (P < 0.001; Figure 2). The RR for OS at the three time points (and associated 95% confidence intervals [CIs]) were 2.02 (1.56-2.60), 1.57 (1.34-1.83) and 1.43 (1.24-1.64) (Table 2 and Figure 2).

Figure 2. Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 2

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Data come from the entire patient population.

Table 2. Meta-analysis of possible associations between PD-L1 expression and overall survival in patients with solid tumors.

Group or subgroup N PD-L1(+/-) 1 year OS 3 year OS 5 year OS
RR (95 % CI) P I2 RR (95 % CI) P I2 RR (95 % CI) P I2
All studies 59 6028/13976 2.02 (1.56-2.60) <0.001 84 1.57 (1.34-1.83) <0.001 91 1.43 (1.24-1.64) <0.001 92
Ethnic subgroups
Asian 35 2211/4126 1.83 (1.61-2.08)* <0.001 49 1.57 (1.39-1.77) <0.001 74 1.44 (1.31-1.58) <0.001 92
Non-Asian 24 3817/9850 1.98 (1.27-3.09) 0.003 90 1.60
(1.18-2.17)		 0.003 95 1.39
(1.08-1.78)		 0.009 95
Tumor origin
Gastrointestinal tumors 24 1778/3206 2.12
(1.45-3.09)		 <0.001 86 1.52 (1.23-1.89) <0.001 91 1.40 (1.17-1.67) <0.001 91
Other tumors 35 4250/10770 1.79 (1.33-2.40) <0.001 86 1.61 (1.30-1.98) <0.001 92 1.47 (1.23-1.75) <0.001 91
Tumor type
Breast cancer 5 1647/5677 1.80 (0.60-5.42) 0.30 79 1.79 (0.77-4.19) <0.18 95 1.80 (0.68-4.73) <0.24 96
Esophageal cancer 4 187/252 1.90 (0.69-5.21) 0.21 70 2.77 (1.78-4.30)* <0.001 48 3.55 (2.63-5.65)* <0.001 0
Gastric carcinoma 7 421/875 2.48 (1.80-3.41)* <0.001 18 1.63
(1.43-1.87)* 		<0.001 32 1.45
(1.18-1.79)		 <0.001 79
Hepatocellular carcinoma 7 321/339 1.87
(1.01-3.46)		 0.04 78 1.40 (0.92-2.15) 0.12 84 1.58
(1.11-2.25)		 0.01 83
Lung cancer 11 1396/2366 1.39 (0.69-2.81) 0.36 88 1.17 (0.84-1.63) 0.35 92 1.16 (0.86-1.57) 0.32 93
Pancreatic cancer 3 61/131 3.43 (2.06-5.73)* <0.001 15 1.48 (1.06-2.06)* 0.02 0 - - -
Merkel cell carcinoma 3 107/272 - - - - - - 1.01 (0.41-2.99) 0.85 89
urinary tract epithelial cell carcinoma 4 197/655 6.24 (3.62-10.74)* <0.001 0 3.43 (1.50-7.84) 0.003 75 1.79 (0.86-3.70) 0.12 82
Oral squamous cell cancer 5 380/537 1.05 (0.58-1.93) 0.87 63 0.95 (0.72-1.26) 0.72 55 1.07 (0.89-1.29)* 0.45 0
Renal cell carcinoma 7 208/572 3.38
(2.13-5.39)* 		<0.001 24 4.14 (2.07-8.26) <0.001 81 2.57
(1.46-4.52)		 <0.001 79
Colorectal cancer 3 788/1609 1.17 (0.27-5.06) 0.84 95 0.94 (0.33-2. 67) 0.90 96 1.16 (0.55-2.45) 0.69 95
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N, number of studies; OS, overall survival; RR, risk ratio; 95% CI, 95% confidence interval

* These meta-analyses were performed using a fixed-effects model. All other meta-analyses were performed using a random-effects model.

Subgroup analysis by tumor type

Given the significant heterogeneity in the meta-analysis involving all 59 studies, we performed a series of subgroup analyses to eamine the possible correlation between PD-L1 expression and OS. PD-L1 expression was associated with worse 1-year OS for the following types of solid tumor (Table 2): gastric cancer, 2.48 (1.80-3.41); renal cell carcinoma, 3.38 (2.13-5.39); and hepatocellular carcinoma, 1.87 (1.01-3.46). PD-L1 expression was associated with worse 3-year OS for the following cancers: esophageal cancer, 2.77 (1.78-4.30); gastric cancer, 1.63 (1.43-1.87); pancreatic cancer, 1.48 (1.06-2.06); and renal cell carcinoma, 4.14 (2.07-8.26). PD-L1 expression was associated with worse 5-year OS for esophageal cancer, 3.55 (2.63-5.65); gastric cancer, 1.45 (1.18-1.79); hepatocellular carcinoma, 1.58 (1.11-2.25); and renal cell carcinoma, 2.57 (1.46-4.52).

Among the subset of 4,984 patients with gastrointestinal tumors, 1,778 (35.6%) were PD-L1-positive and 3,206 (64.4%) were PD-L1-negative. PD-L1 expression was associated with significantly worse OS at 1 year (P = 0.004), 3 years (P = 0.005), and 5 years (P = 0.002; Figures 3 and 7). The corresponding RRs and 95% CIs were 2.12(1.45-3.09), 1.52 (1.23-1.89), and 1.40 (1.17-1.67) (Table 2).

Figure 3. Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 3

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Data come from the subset of patients with gastrointestinal tumors.

Figure 7. Forrest plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 7

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Data come from the subset of patients with gastrointestinal tumors.

Among the subset of 4,309 patients with non-gastrointestinal tumors, 2,298 (53.3%) were PD-L1-positive and 1,404 (59.3%) were PD-L1-negative. PD-L1 expression was associated with significantly worse OS at 1 year (P = 0.017), 3 years (P = 0.010) and 5 years (P = 0.003; Figures 4 and 8). The corresponding RRs and 95% CIs were 1.79 (1.33-2.40), 1.61 (1.30-1.98), and 1.47 (1.23-1.75) (Table 2).

Figure 4. Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 4

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Data come from the subset of patients with non-gastrointestinal tumors.

Figure 8. Forrest plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 8

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Data come from the subset of patients with non-gastrointestinal tumors.

Subgroup analysis by patient ethnicity

Among the subset of 6,337 Asian patients, 2,211 were PD-L1-positive and 4,126 were PD-L1-negative. PD-L1 expression was associated with significantly lower OS at 1 year (P = 0.030), 3 years (P = 0.005) and 5 years (P = 0.005; Figures 5 and 9). The corresponding RRs and 95% CIs were 1.86 (1.61-2.08), 1.57 (1.39-1.77), and 1.44 (1.31-1.58) (Table 2).

Figure 5. Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 5

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Data come from the subset of Asian patients.

Figure 9. Forrest plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 9

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Data come from the subset of Asian patients.

Among the subset of 13,667 non-Asian patients, 3,817 were PD-L1-positive and 9,850 were PD-L1-negative. PD-L1 expression was associated with significantly lower OS at 1 year (P = 0.048), 3 years (P = 0.040) and 5 years (P = 0.024; Figures 6 and 10). The corresponding RRs and 95% CIs were 1.98 (1.27-3.09), 1.60 (1.18-2.17), and 1.39 (1.08-1.78) (Table 2).

Figure 6. Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 6

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Data come from the subset of non-Asian patients.

Figure 10. Forrest plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression.

Figure 10

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Data come from the subset of non-Asian patients.

DISCUSSION

While studies published more than a decade ago established that PD-L1 promotes cancer immune escape [82, 83] and that blocking PD-L1 can improve the anti-tumor efficacy of anti-tumor responses [84–86], whether PD-L1 expression by solid tumors negatively affects patient prognosis remains unclear. Here we reviewed 59 studies involving 20,004 patients with 11 types of solid tumors and found strong evidence that PD-L1 expression is associated with significantly lower OS at 1, 3 and 5 years. This effect was observed in meta-analyses involving all patients as well as several subgroups of patients stratified by ethnicity and tumor type.

PD-L1 positive expression is associated with viral infection and chronic inflammation [87]. Expression of PD-L1 and/or PD-1 has been described for numerous types of cancers associated with viral infection [88], including polycyclic virus-associated Merkel cell carcinoma [89], hepatitis B virus-associated hepatocellular carcinoma [33], human papillomavirus-associated head and neck cancer, and Epstein-Barr virus-related nasopharyngeal carcinoma [90]. In patients with hepatocellular carcinoma, PD-L1 expression was significantly higher in tumor macrophages than in matched normal tissues, and expression correlated with tumor grade [25].

Our results are consistent with previous reports that PD-L1 expression is associated with worse 5-year outcome in patients with gastrointestinal carcinomas such as esophageal cancer and gastric cancer [70, 79] as well as colorectal cancer [25]. The precise mechanisms whereby PD-L1 expression may worsen prognosis are unknown; When PD-1 binds to the ligand PD-L1 (B7-H1) expressed on the surface of tumors, PD-1 has been shown to promote tumor cell-specific T cell inactivation or apoptosis [12].

The results of this meta-analysis should be interpreted cautiously because of several limitations. One is the lack of a standardized assay and cut-off value for classifying patients as PD-L1-positive. This may help explain the high heterogeneity observed across the included studies. Another limitation is our exclusion of gray literature, which may have increased the risk of publication bias and selection bias.

Despite these limitations, this large meta-analysis provides strong evidence that expression of PD-L1 may be a meaningful index for predicting prognosis in a wide variety of patients with solid tumors. These findings justify more focused prognostic studies in well-defined patient populations in which a panel of clinically relevant outcomes beyond only OS are considered.

MATERIALS AND METHODS

Literature search

PubMed, EMBASE, Web of Science and EBSCO were searched through 15 January 2017 to identify cohort and case-control studies examining the relationship between PD-L1 expression and prognosis of patients with solid tumors. The following search terms were used: programmed death-ligand 1, PD-L1, B7-H1, CD274 and solid tumor.

Inclusion and exclusion criteria

To be included in our meta-analysis, studies had to involve (1) primary solid tumors in human patients; (2) The main content of the articles is to analyze the relationship between the expression of PD-L1 and the prognosis of solid tumors in patients; (3) a hospital-based or population-based case-control or cohort design, regardless of sample size; (4) immunohistochemical assay of PD-L1 expression as high and low PD-L1 expression; (5) all patients underwent surgery; and (6) adequate reporting of overall survival (OS) data. When eligible studies involved overlapping patient populations, only the most recent or complete report was included. Studies were excluded if they were letter, summary of meeting and review; if they were published in a language other than English; or if they failed to report adequate data; or they investigated metastatic tumors. Gray literature (Reports and papers that were not published in PubMed, EMBASE, Web of Science and EBSCO) was not included into this study. Reference lists within identified articles were also searched manually to identify additional articles.

Meta-analysis outcomes

The primary outcome in the meta-analysis was OS. This outcome was compared between patients showing high or positive PD-L1 expression and patients showing low or no expression, as defined within the individual studies.

Data collection

Two researchers (P.-C.Y, X.X) independently screened studies for inclusion. Disagreements were resolved by discussion and, when necessary, consultation with a third author (S.Z). The first author's name, year of publication, country, number of patients, and tumor type were extracted from each study, and OS results for 1, 3 and 5 years were extracted from tables or Kaplan-Meier curves.

Statistical analysis

Forest plots of OS were generated using RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark). Weighted risk ratio (RR) estimates were generated from pooled data using Mantel-Haenszel random-effects meta-analysis, unless no statistically heterogeneity, in which case fixed-effects meta-analysis was performed. Statistical heterogeneity in meta-analyses was assessed using Cochrane's Q and I2statistics. Survival results were analyzed using scatter plots generated in Prism 5 (Graphpad Software, San Diego, USA). The results for different patient groups were compared using the log-rank test. The threshold of statistical significance was defined as P < 0.05.

Footnotes

CONFLICTS OF INTEREST

The authors have declared that no competing interests exist.

FUNDING

This work was supported by Guangxi University of Science and Technology Research Projects (KY2015LX056), the Self-Raised Scientific Research Fund of the Ministry of Health of Guangxi Province (Z2016512, Z2015621, Z2015601, GZZC15-34, Z2014241), the Graduate Course Construction Project of Guangxi Medical University (YJSA2017014), and the the National Science and Technology Major Special Project (2012ZX10002010001009).

Author contributions

X.X, J.-H.Z and L.L conceived the study; P.-C.Y collected and analyzed the data; X.X drafted the manuscript; all authors have read and approved the final version to be published.

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