The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastrointestinal tract cancer: a systematic review and meta-analysis
OncoTargets and Therapy
The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastro intestinal tract cancer : a systematic review and metaanalysis
0 Department of laboratory Medicine, Yantai Yuhuangding hospital , Yantai, People's republic of china
8 1 0 2 - l u J - 2 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon PowerdbyTCPDF(ww.tcpdf.org) Baohua huang* lei chen* cuixia Bao chengming sun Jie li lipeng Wang Xia Zhang
O r i g i n a l; r e s e a r c h
*These authors contributed equally
to this work
Background: Programmed cell death 1 ligand 1 (PD-L1) expression has been observed in
various malignancies. However, the association between PD-L1 expression and the survival
of patients with gastrointestinal tract cancer remains controversial. Besides, the rate of PD-L1
positivity on tumor cells of digestive tract cancer is not clear. Thus, we performed a meta-analysis
by incorporating all available evidence to evaluate the rate of PD-L1 positivity and the overall
survival (OS) according to PD-L1 status in patients with gastrointestinal tract cancer.
Methods: Electronic databases were searched for eligible literature. Hazard ratios (HRs) for
OS with 95% confidence intervals (CIs) according to the expression status of PD-L1
evaluated by immunohistochemistry were extracted. The outcomes were synthesized based on a
Results: Fifteen studies (only nine reported OS) that involved 2,993 gastrointestinal tract cancer
patients stratified by PD-L1 status were eligible for inclusion in our study. We found the
PD-L1positive expression rate was 0.495 (95% CI 0.415–0.576) if 10% was taken as the cut-off value.
When the H-score method was used to evaluate PD-L1 expression, it showed that the PD-L1
positive rate was 0.639 (95% CI 0.490–0.765) if the cut-off value was ,50, which was higher than
when using .50 as the cut-off point (0.449, 95% CI 0.417–0.483). Additionally, PD-L1-positive
gastrointestinal tract cancer patients were associated with significantly poorer OS when compared
to negative ones (HR 1.61, 95% CI 1.10–2.35, P=0.014). Subgroup analysis presented similar
significant results in patients with esophageal cancer (HR 2.56, 95% CI 1.55–4.21, P,0.001).
Conclusion: The positive expression rate of PD-L1 was nearly 50% no matter which method
for immunohistochemistry evaluation we chose. Additionally, positive PD-L1 expression
status in tumor cells is a risk factor for prognosis of gastrointestinal tract cancer, especially
Keywords: prognosis, esophageal cancer, immunohistochemistry, PD-L1-positive
Gastrointestinal tract cancer refers to malignant conditions of the gastrointestinal
tract, including of the esophagus, stomach, small intestine, large intestine, rectum,
and anus. Among those cancer patients, colorectal carcinoma, gastric cancer, and
esophageal cancer are common types (the third, fourth, and sixth most-frequently
diagnosed malignancies, respectively) globally.1–3 Although recent advances in
multidisciplinary therapies have improved treatment outcomes, the overall prognosis
for gastrointestinal tract cancer remains poor. It is well known that the development
and prognosis of malignant tumors are closely related to
host immune functions.4 Thus, novel therapeutic strategies,
especially immunotherapy, are needed to be developed and
It has been identified that immune escape plays an
important role in tumor progression.5 Improved understanding of the
molecular mechanisms that govern the host response to tumors
has led to the identification of checkpoint signaling pathways
that limit the anticancer immune response.6 A particularly
important immune checkpoint that mediates tumor-induced
immune suppression is the binding of programmed death 1
(PD-1) expressed on tumor-infiltrating lymphocytes and its
ligand 1 (PD-L1) expressed on tumor cells.7 PD-L1 has been
reported to inhibit the proliferation of activated T-cells and
induce the apoptosis of T-cells to form and maintain an
immunosuppressive microenvironment since PD-L1 can recognize
and bind the PD-1 on tumor-infiltrating lymphocytes.8
PD-L1 expression has been observed in various
malig.vdoep lsyeon nPaDn-cLie1so. vMeroerxeporveesrs,iosnevinerdailcamteestaa-panoaolrypsreosghnaovseispfororvpeadtiethnatst
//:ww lano with non-small cell lung cancer.9–11 However, the association
tsp rse between PD-L1 expression and the survival of patients with
rom oF gastrointestinal tract cancer remains controversial. Besides,
fd the rate of PD-L1 positivity on tumor cells of digestive tract
dea cancer is not clear. Therefore, the expression status and
proglnow nostic significance of PD-L1 require further comprehensive
yod study to clarify. Thus, we performed a meta-analysis by
incorrape porating all available evidence to evaluate the expression rate
hT of PD-L1 and the overall survival (OS) according to PD-L1
dna status in patients with gastrointestinal tract cancer.
Materials and methods
Our institutions Ethics Committee has exempted our study
from Institutional Review Board approval as our study
involves exclusively preexisting anonymous data. The
preferred reporting items for systematic reviews and
metaanalyses (PRISMA) statement for reporting systematic
reviews recommended by the Cochrane Collaboration was
followed for conducting this meta-analysis. Two authors
independently carried out a comprehensive systematic search for
published articles or abstracts by searching through PubMed,
Embase, Scopus, and the Cochrane Library from inception
to April 2015. Searches were limited to human studies, using
a combination of the terms “PD-L1”, “CD274”, “B7-H1”,
“programmed cell death 1 ligand 1”, “gastrointestinal”,
“esophageal”, “gastric”, “colorectal”, “outcome”, “survival”,
and “prognosis”. We also manually reviewed relevant
reference lists and reviews. There were no language restrictions.
inclusion and exclusion criteria
Studies meeting the following criteria were eligible for the
single-arm meta-analysis of PD-L1-positive expression rate
on tumor cells: (
) cohort studies which investigated PD-L1
expression level in gastrointestinal tract cancer patients;
) the expression level of PD-L1 was tested by
immunohistochemistry (IHC) staining in the tissue specimens; (
samples of PD-L1 positive and PD-L1 negative were
available. Moreover, studies in the meta-analysis that focused on
patients’ survival according to PD-L1 status met the
following criteria: (
) studies meeting the criteria of meta-analysis
for PD-L1-positive expression rate; (
) survival data stratified
by PD-L1 status was available. Studies that failed to meet
the inclusion criteria were excluded.
Outcome measures, data extraction,
and quality assessment
The primary outcome for this meta-analysis was PD-L1-positive
expression rate and OS. OS data were extracted in the form of
hazard ratios (HRs) with the corresponding 95% confidence
interval (CI). If the HR was not displayed directly, it was estimated
according to the methods described by a previously published
article.12 The data collection and assessment of
methodological quality followed the quality of reporting of meta-analyses
(QUORUM) and the Cochrane Collaboration guidelines (http://
www.cochrane.de). The following main items were abstracted
from the included studies: author, year, tumor type, IHC
evaluation method and cut-off value, sample size of total patients and
PD-L1-positive group, and survival data. Two reviewers used
the modified Newcastle–Ottawa scale to assess these studies.13
All investigators discussed and resolved all discrepancies in the
extracted data. All of the eligible studies were of high quality.
All calculations for PD-L1-positive expression rate on tumor
cells were performed using Meta-Analyst Beta (v 3.13; Tufts
Medical Center, Boston, MA, USA). HRs for OS with 95%
CIs according to the expression status of PD-L1 was pooled
using STATA (v 11.0; StataCorp, College Station, TX,
USA). Heterogeneity across the incorporated studies was
assessed with a forest plot and the inconsistency statistic (I2).
A random-effects model was employed in case of potential
heterogeneity and to avoid underestimation of standard errors
of pooled estimates in this meta-analysis. Subgroup analysis
was conducted according to IHC evaluation method and
cut-off value and tumor type. An HR that was greater than
1 reflected shorter OS for PD-L1-positive patients. All CIs had
two-sided probability coverage of 95%. A statistical test with
a P-value less than 0.05 was considered as significant.
An extensive search strategy was made to minimize the
potential publication bias. Graphical funnel plots were
generated to visually assess publication bias. The statistical method
to detect funnel plot asymmetry was Begg’s test.14
In total, 574 records were identified according to the search
strategy. Finally, we enrolled 15 studies15–29 that involved
2,993 gastrointestinal tract cancer patients (1,461/1,532
cases for PD-L1 positive/negative) with available PD-L1
expression data stratified by PD-L1 status. Nine of the
studies16–19,21,23,26–28 reported HRs for OS as a clinical outcome.
Figure 1 summarizes the flow chart of study selection. Our
study covered three major types of gastrointestinal tract
cancer, esophageal cancer, gastric cancer, and colorectal
carcinoma. The H-score was one of the most common
methods used to evaluate the expression of PD-L1 in the tumor
cells among the included articles, as well as the percentage
of positively stained cells. The characteristics of the enrolled
studies are shown in Table 1.
singlearm metaanalysis of positive
expression rate of PDl1
After stratifying the enrolled studies according to IHC
evaluation method and cut-off value, we found the PD-L1-positive
expression rate was 0.495 (95% CI 0.415–0.576) if 10%
was taken as the cut-off value. When the H-score method
was used to evaluate PD-L1 expression, it showed that the
PD-L1 positive rate was 0.639 (95% CI 0.490–0.765) if the
cut-off value was ,50, which was higher than when .50
was used as the cut-off point (0.449, 95% CI 0.417–0.483)
Metaanalysis of PDl1 positive versus
PDl1 negative in terms of Os
Overall, positive expression of PD-L1 in the tumor cells of
gastrointestinal tract cancer patients was associated with a
significantly poorer OS than negative expression (HR 1.61,
95% CI 1.10–2.35, P=0.014) (Figure 3).
subgroup analyses, sensitivity analyses,
and publication bias
The H-score evaluation method showed inferior survival
in the PD-L1-positive group if we took ,50 as the
cutoff value (HR 1.75, 95% CI 1.33–2.31, P,0.001). The
results were similar when using .50 as the cut-off value
(HR 1.79, 95% CI 0.69–4.62, P=0.231). However, an only
slightly numerical adverse prognostic effect of
PD-L1positive expression was presented if 10% was taken as the
cut-off value using the percentage method (HR 1.05, 95%
CI 0.42–2.61, P=0.919) (Figure 4). Additionally, when
stratifying studies according to tumor type, we observed
that meta-analysis presented significant poorer OS in the
PD-L1-positive group of patients with esophageal cancer
(HR 2.56, 95% CI 1.55–4.21, P,0.001). Similar
numerical survival benefits were found in the PD-L1 negative
Figure 1 Flow chart of study selection.
Abbreviation: PDl1, programmed cell death 1 ligand 1.
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Figure 2 (Continued)
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0.366 (0.278, 0.464)
some survival data of the HRs from the available data or
Kaplan–Meier curves, which may have compromised the
precision of the data. Secondly, cut-off values
distinguishing positive and negative expression of PD-L1 determined
by IHC evaluation and the primary antibodies varied in
different types of tumors, which might cause
heterogeneity of the overall results. The subgroup results should have
addressed some concerns. Thirdly, we were not able to
evaluate the expression rate of PD-L1 stratified by tumor
type in subgroup analysis due to inconsistent IHC
evaluations. Fourthly, we were unable to determine whether a
correlation exists between positive PD-L1 expression and
the clinical characteristics of gastrointestinal tract cancer.
In addition, most of the eligible studies failed to provide
data regarding progression-free survival or recurrence-free
survival, so we only extracted OS data in our meta-analysis.
Besides, scientists might prefer to only report the positive
results of a prognostic biomarker, leading to the existence
of potential publication bias. Further studies are warranted
to address the above issues.
Regardless of the described limitations, this
comprehensive analysis statistically confirmed almost half of all
gastrointestinal tract cancer patients positively expressed
PD-L1 in tumor cells and those PD-L1 positive patients
were associated with significantly shorter OS, especially
in esophageal cancer. A recent study has confirmed that
positive PD-L1 expression is correlated with the improved
efficacy of pembrolizumab, a drug marketed by Merck that
targets the PD-1 receptor, in patients with advanced
nonsmall-cell lung cancer.31 These results hint that, in clinical
trials using anti-PD-L1 or anti-PD-1 antibodies as cancer
immunotherapy, enrollment might also be preferentially
carried out on patients with gastrointestinal tract cancer,
especially esophageal cancer. Furthermore, more efforts
should be made to investigate which cut-off value is the
best for differentiating real PD-L1-positive patients with
gastrointestinal tract cancer who would get survival benefit
from PD-1/PD-L1 blockers.
In this meta-analysis, we found the positive expression
rate of PD-L1 was nearly 50%, no matter which method
for IHC evaluation we chose. Additionally, we found
positive PD-L1 expression status in tumor cells is a risk factor
for prognosis in gastrointestinal tract cancer, especially in
This study was supported by the National Natural Science
Foundation of China (number 81202069).
The funder had no role in the study design, data
collection and analysis, decision to publish, or preparation of this
The authors declare no conflicts of interest in this work.
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OncoTargets and Therapy is an international, peer-reviewed, open
access journal focusing on the pathological basis of all cancers, potential
targets for therapy and treatment protocols employed to improve the
management of cancer patients. The journal also focuses on the impact
of management programs and new therapeutic agents and protocols on
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