Oncotarget

Research Papers:

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

PDF |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:5058-5072. https://doi.org/10.18632/oncotarget.23580

Metrics: PDF 1636 views  |   HTML 2648 views  |   ?  

Xiao Xiang, Peng-Cheng Yu, Di Long, Xiao-Li Liao, Sen Zhang, Xue-Mei You, Jian-Hong Zhong and Le-Qun Li _

Abstract

Xiao Xiang1, Peng-Cheng Yu2, Di Long2, Xiao-Li Liao1, Sen Zhang2, Xue-Mei You1, Jian-Hong Zhong1 and Le-Qun Li1

1Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China

2Department of Colorectal Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China

Correspondence to:

Le-Qun Li, email: xitongpingjia@163.com

Jian-Hong Zhong, email: zhongjianhong66@163.com, zhongjianhong@gxmu.edu.cn

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

Received: March 22, 2017     Accepted: December 13, 2017     Published: December 22, 2017

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.


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 [911]. 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 [1014]. 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 [1519].

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 [2022]. 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.

Flow chart of study selection.

Figure 1: Flow chart of study selection.

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 [2341], France [42], New Zealand [43, 44], Brazil [45], Australia [46], Canada [47, 48], Italy [49], Germany [50, 51], United States [5265], Japan [6674], South Korea [7578], 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

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).

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

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

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).

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

Figure 3: Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression. Data come from the subset of patients with gastrointestinal tumors.

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

Figure 4: Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression. Data come from the subset of patients with non-gastrointestinal tumors.

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

Figure 5: Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression. Data come from the subset of Asian patients.

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

Figure 6: Scatter plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression. Data come from the subset of non-Asian patients.

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

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

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

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

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

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

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

Figure 10: Forrest plot of OS at 1, 3 and 5 years for patients positive or negative for PD-L1 expression. 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 [8486], 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.

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.

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).

REFERENCES

1. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature reviews. Immunology. 2013; 13:227-242.

2. Perez-Gracia JL, Labiano S, Rodriguez-Ruiz ME, Sanmamed MF, Melero I. Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Current Opin Immunol. 2014; 27:89-97.

3. Xiang X, Qin HG, You XM, Wang YY, Qi LN, Ma L, Xiang BD, Zhong JH, Li LQ. Expression of P62 with hepatocellular carcinoma involving hepatitis B virus infection and aflatoxin B1 exposure. Cancer Med. 2017; 6:2357-2369

4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100:57-70.

5. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000; 192:1027-1034.

6. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001; 2:261-268.

7. Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol. 2011; 350:17-37.

8. Zha Y, Blank C, Gajewski TF. Negative regulation of T-cell function by PD-1. Crit Rev Immunol. 2004; 24:229-237.

9. D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, Tibaldi C, Minuti G, Salvini J, Coppi E, Chella A, Fontanini G, Filice ME, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015; 112:95-102.

10. Faraj SF, Munari E, Guner G, Taube J, Anders R, Hicks J, Meeker A, Schoenberg M, Bivalacqua T, Drake C, Netto GJ. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology. 2015; 85:703.e701-706.

11. Yamane H, Isozaki H, Takeyama M, Ochi N, Kudo K, Honda Y, Yamagishi T, Kubo T, Kiura K, Takigawa N. Programmed cell death protein 1 and programmed death-ligand 1 are expressed on the surface of some small-cell lung cancer lines. Am J Cancer Res. 2015; 5:1553-1557.

12. Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, Rossille D, Maudelonde T, Fest T, Alix-Panabières C. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015; 9:1773-1782.

13. Chang YL, Yang CY, Lin MW, Wu CT, Yang PC. PD-L1 is highly expressed in lung lymphoepithelioma-like carcinoma: a potential rationale for immunotherapy. Lung Cancer. 2015; 88:254-259.

14. Tsai KK, Zarzoso I, Daud AI. PD-1 and PD-L1 antibodies for melanoma. Hum Vaccin Immunother. 2014; 10:3111-3116.

15. Brower V. Anti-PD-L1 antibody active in metastatic bladder cancer. Lancet Oncol. 2015; 16:e11.

16. Gettinger S, Herbst RS. B7-H1/PD-1 blockade therapy in non-small cell lung cancer: current status and future direction. Cancer J. 2014; 20:281-289.

17. Xiang X, Zhong JH, Wang YY, You XM, Ma L, Xiang BD, Li LQ. Distribution of tumor stage and initial treatment modality in patients with primary hepatocellular carcinoma Clin Transl Oncol. 2017; 19:891-897

18. Barbee MS, Ogunniyi A, Horvat TZ, Dang TO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann Pharmacother. 2015; 49:907-937.

19. McDermott J, Jimeno A. Pembrolizumab: PD-1 inhibition as a therapeutic strategy in cancer. Drugs Today (Barc). 2015; 51:7-20.

20. Gunturi A, McDermott DF. Nivolumab for the treatment of cancer. Expert Opin Investig Drugs. 2015; 24:253-260.

21. Errico A. Immunotherapy: PD-1-PD-L1 axis: efficient checkpoint blockade against cancer. Nat Rev Clin Oncol. 2015; 12:63.

22. Zhong JH, Luo CP, Zhang CY, Li LQ. Strengthening the case that elevated levels of programmed death ligand 1 predict poor prognosis in hepatocellular carcinoma patients. J Hepatocell Carcinoma. 2017; 4:11-13.

23. Qin T, Zeng YD, Qin G, Xu F, Lu JB, Fang WF, Xue C, Zhan JH, Zhang XK, Zheng QF, Peng RJ, Yuan ZY, Zhang L, Wang SS. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget. 2015; 6:33972-33981. https://doi.org/10.18632/oncotarget.5583.

24. Shi SJ, Wang LJ, Wang GD, Guo ZY, Wei M, Meng YL, Yang AG, Wen WH. 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.

25. Zhu J, Chen L, Zou L, Yang P, Wu R, Mao Y, Zhou H, Li R, Wang K, Wang W, Hua D, Zhang X. MiR-20b, -21, and -130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer. Hum Immunol. 2014; 75:348-353.

26. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004; 4:336-347.

27. Geng Y, Wang H, Lu C, Li Q, Xu B, Jiang J, Wu C. 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.

28. Hou J, Yu Z, Xiang R, Li C, Wang L, Chen S, Li Q, Chen M, Wang L. 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.

29. Zheng Z, Bu Z, Liu X, Zhang L, Li Z, Wu A, Wu X, Cheng X, Xing X, Du H, Wang X, Hu Y, Ji J. Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. 2014; 26:104-111.

30. Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009; 15:971-979.

31. Kan G, Dong W. The expression of PD-L1 APE1 and P53 in hepatocellular carcinoma and its relationship to clinical pathology. Eur Rev Med Pharmacol Sci. 2015; 19:3063-3071.

32. Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009; 69:8067-8075.

33. Zeng Z, Shi F, Zhou L, Zhang MN, Chen Y, Chang XJ, Lu YY, Bai WL, Qu JH, Wang CP, Wang H, Lou M, Wang FS, et al. Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One. 2011; 6:e23621.

34. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012; 98:751-755.

35. Jiang L, Wang L, Li PF, Zhang XK, Chen JW, Qiu HJ, Wu XD, Zhang B. Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma. OncoTargets Ther. 2015; 8:1451-1457.

36. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. 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.

37. Song Z, Yu X, Cheng G, Zhang Y. Programmed death-ligand 1 expression associated with molecular characteristics in surgically resected lung adenocarcinoma. J Transl Med. 2016; 14:188.

38. Zhang Y, Wang L, Li Y, Pan Y, Wang R, Hu H, Li H, Luo X, Ye T, Sun Y, Chen H. Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma. OncoTargets Ther. 2014; 7:567-573.

39. Chen XL, Yuan SX, Chen C, Mao YX, Xu G, Wang XY. [Expression of B7-H1 protein in human pancreatic carcinoma tissues and its clinical significance]. [Article in Chinese]. Ai zheng. 2009; 28:1328-1332.

40. Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 expressions in pancreatic carcinoma. World J Surg. 2010; 34:1059-1065.

41. Wang Y, Zhuang Q, Zhou S, Hu Z, Lan R. Costimulatory molecule B7-H1 on the immune escape of bladder cancer and its clinical significance. J Huazhong Univ Sci Technolog Med Sci. 2009; 29:77-79.

42. Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015; 6:5449-5464. https://doi.org/10.18632/oncotarget.3216.

43. Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011; 117:2192-2201.

44. Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, Muraro MG, Zajac P, Zanetti R, Gillanders WE, Weber WP, Soysal SD. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014; 146:15-24.

45. Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol. 2016; 47:78-84.

46. Beckers RK, Selinger CI, Vilain R, Madore J, Wilmott JS, Harvey K, Holliday A, Cooper CL, Robbins E, Gillett D, Kennedy CW, Gluch L, Carmalt H, et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology. 2016; 69:25-34.

47. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Chen L, Zincke H, Blute ML, Leibovich BC, Kwon ED. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005; 104:2084-2091.

48. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Kwon ED. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007; 13:1757-1761.

49. Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, Zlobec I, Eppenberger-Castori S, Tzankov A, Rosso R, Zuber M, Muraro MG, Amicarella F, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer. 2013; 49:2233-2242.

50. Abbas M, Steffens S, Bellut M, Eggers H, Großhennig A, Becker JU, Wegener G, Schrader AJ, Grünwald V, Ivanyi P. Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC). Med Oncol. 2016; 33:80.

51. Loos M, Langer R, Schuster T, Gertler R, Walch A, Rauser S, Friess H, Feith M. Clinical significance of the costimulatory molecule B7-H1 in Barrett carcinoma. Ann Thorac Surg. 2011; 91:1025-1031.

52. Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, Blute ML, Sebo TJ, Cheville JC, Parker AS, Kwon ED. Survivin and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell carcinoma. Clinical Cancer Res. 2007; 13:1749-1756.

53. Choueiri TK, Fay AP, Gray KP, Callea M, Ho TH, Albiges L, Bellmunt J, Song J, Carvo I, Lampron M, Stanton ML, Hodi FS, McDermott DF, et al. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol. 2014; 25:2178-2184.

54. Thompson RH, Gillett MD, Cheville JC, Callea M, Ho TH, Albiges L, Bellmunt J, Song J, Carvo I, Lampron M, Stanton ML, Hodi FS, McDermott DF, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004; 101:17174-17179.

55. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, Blute ML, Sebo TJ, Cheville JC, Kwon ED. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006; 66:3381-3385.

56. Cooper WA, Tran T, Vilain RE, Madore J, Selinger CI, Kohonen-Corish M, Yip P, Yu B, O'Toole SA, McCaughan BC, Yearley JH, Horvath LG, Kao S, et al. PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma. Lung Cancer. 2015; 89:181-188.

57. Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014; 94:107-116.

58. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012; 4:127ra137.

59. Boorjian SA, Sheinin Y, Crispen PL, Farmer SA, Lohse CM, Kuntz SM, Leibovich BC, Kwon ED, Frank I. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res. 2008; 14:4800-4808.

60. Xylinas E, Robinson BD, Kluth LA, Volkmer BG, Hautmann R, Küfer R, Zerbib M, Kwon E, Thompson RH, Boorjian SA, Shariat SF. Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder. Eur J Surg Oncol. 2014; 40:121-127.

61. Oliveira-Costa JP, de Carvalho AF, da Silveira da GG, Amaya P, Wu Y, Park KJ, Gigliola MP, Lustberg M, Buim ME, Ferreira EN, Kowalski LP, Chalmers JJ, Soares FA, et al. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. Oncotarget. 2015; 6:20902-20920. https://doi.org/10.18632/oncotarget.3939.

62. Ukpo OC, Thorstad WL, Lewis JS Jr. B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2013; 7:113-121.

63. Qing Y, Li Q, Ren T, Xia W, Peng Y, Liu GL, Luo H, Yang YX, Dai XY, Zhou SF, Wang D. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther. 2015; 9:901-909.

64. Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, Reddy S, Kleiner D, Fishbein T, Johnson L, Island E, Satoskar R, Banovac F, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016; 4:419-430.

65. Eto S, Yoshikawa K, Nishi M, Higashijima J, Tokunaga T, Nakao T, Kashihara H, Takasu C, Iwata T, Shimada M. Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection. Gastric Cancer. 2016; 19:466-471.

66. Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T, Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T, Nakanishi Y, Okamoto I. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol. 2014; 25:1935-1940.

67. Inamura K, Yokouchi Y, Sakakibara R, Kobayashi M, Subat S, Ninomiya H, Nagano H, Nomura K, Okumura S, Ishikawa Y. Relationship of tumor PD-L1 expression with EGFR wild-type status and poor prognosis in lung adenocarcinoma. Jpn J Clin Oncol. 2016; 46:935-941.

68. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010; 116:1757-1766.

69. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007; 56:1173-1182.

70. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005; 11:2947-2953.

71. Tanaka K, Miyata H, Sugimura K, Kanemura T, Hamada-Uematsu M, Mizote Y, Yamasaki M, Wada H, Nakajima K, Takiguchi S, Mori M, Doki Y, Tahara H. Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy. Cancer Sci. 2016; 107:726-733.

72. Tamura T, Ohira M, Tanaka H, Muguruma K, Toyokawa T, Kubo N, Sakurai K, Amano R, Kimura K, Shibutani M, Maeda K, Hirakawa K. Programmed death-1 ligand-1 (PDL1) expression is associated with the prognosis of patients with stage II/III gastric cancer. Anticancer Res. 2015; 35:5369-5376.

73. Umemoto Y, Okano S, Matsumoto Y, Nakagawara H, Matono R, Yoshiya S, Yamashita Y, Yoshizumi T, Ikegami T, Soejima Y, Harada M, Aishima S, Oda Y, et al. Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy. J Gastroenterol. 2015; 50:65-75.

74. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007; 13:2151-2157.

75. Kim S, Kim MY, Koh J, Go H, Lee DS, Jeon YK, Chung DH. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Eur J Cancer. 2015; 51:2698-2707.

76. Kim HS, Lee JY, Lim SH, Park K, Sun JM, Ko YH, Baek CH, Son YI, Jeong HS, Ahn YC, Lee MY, Hong M, Ahn MJ. Association between PD-L1 and HPV status and the prognostic value of PD-L1 in oropharyngeal squamous cell carcinoma. Cancer Res Treat. 2016; 48:527-536.

77. Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol. 2011; 47:1148-1153.

78. Jung HI, Jeong D, Ji S, Ahn TS, Bae SH, Chin S, Chung JC, Kim HC, Lee MS, Baek MJ. Overexpression of PD-L1 and PD-L2 is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma. Cancer Res Treat. 2017; 49:246-254.

79. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006; 108:19-24.

80. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC. 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.

81. Lin YM, Sung WW, Hsieh MJ, Tsai SC, Lai HW, Yang SM, Shen KH, Chen MK, Lee H, Yeh KT, Chen CJ. High PD-L1 expression correlates with metastasis and poor prognosis in oral squamous cell carcinoma. PLoS One. 2015; 10:e0142656.

82. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8:793-800.

83. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002; 99:12293-12297.

84. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003; 9:562-567.

85. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, Hirano F, Lin W, Kasperbauer JL, Ballman KV, Chen L. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003; 63:6501-6505.

86. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004; 64:1140-1145.

87. Abdel-Magid AF. Inhibitors of the PD-1/PD-L1 Pathway Can Mobilize the Immune System: An Innovative Potential Therapy for Cancer and Chronic Infections. ACS Med Chem Lett. 2015; 6:489-490.

88. Fang W, Zhang J, Hong S, Zhan J, Chen N, Qin T, Tang Y, Zhang Y, Kang S, Zhou T, Wu X, Liang W, Hu Z, et al. EBV-driven LMP1 and IFNgamma up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. Oncotarget. 2014; 5:12189-12202. https://doi.org/10.18632/oncotarget.2608.

89. Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, Xu H, Nayar SK, Wang TS, Sidransky D, Anders RA, Topalian SL, Taube JM. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res. 2013; 1:54-63.

90. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013; 73:1733-1741.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23580