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, Sep 2015

The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastro­intestinal tract cancer: a systematic review and meta-analysis Baohua Huang,* Lei Chen,* Cuixia Bao, Chengming Sun, Jie Li, Lipeng Wang, Xia Zhang Department of Laboratory Medicine, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China *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 random-effects model.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-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 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 esophageal cancer. Keywords: prognosis, esophageal cancer, immunohistochemistry, PD-L1-positive expression rate

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.dovepress.com/getfile.php?fileID=27043

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 random-effects model. 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 esophageal cancer. Keywords: prognosis, esophageal cancer, immunohistochemistry, PD-L1-positive expression rate Introduction 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 established.4 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 w u //: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 th rp 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. s t e g r a T o c n O Materials and methods literature search 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. 2618 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: ( 1 ) cohort studies which investigated PD-L1 expression level in gastrointestinal tract cancer patients; ( 2 ) the expression level of PD-L1 was tested by immunohistochemistry (IHC) staining in the tissue specimens; ( 3 ) 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: ( 1 ) studies meeting the criteria of meta-analysis for PD-L1-positive expression rate; ( 2 ) 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. statistical analysis 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. 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 w u /ww lan /: o tsp rse th rp Publication bias 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 Results eligible studies 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) (Figure 2). 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. submit your manuscript | www.dovepress.com Dovepress 2619 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 e r . p ly e n v o o d e . s w u w l a /w n /: o s rs tp e t p h r mo o F r f t i m I i l C 7 7 8 p 9 6 7 3 1 1 ,e ) l % a ( p f a .6 .5 .1 .7 a .0 a .3 a a .8 .5 .7 a e m Begg’s test are shown in Figure S1. U o n 5 4 6 2 n 1 n 2 n n 0 3 2 n *ga m .s ra t ll g i e o c r m I p li C ive ,1 Discussion re 5% its -L w 9 1 3 6 1 7 1 0 9 p P For patients with gastrointestinal tract malignancies, the 7 6 3 8 5 o D o f a .5 .0 .2 .1 a .4 a .1 a a .8 .0 .1 a l; L o n 1 1 1 1 n 0 n 1 n n 0 1 1 n 0% av 0 iv association of the expression of PD-L1 and their prognosis 1 r r – u fo ,1 lls remains unclear. In addition, the positive expression rate b 7 1 9 1 0 a 2 5 4 5 5 4 5 1 4 0 r R S a .9 .1 .7 .6 a .6 a .6 a a .8 .6 .7 a –1 ve of PD-L1 in the tumor cells of digestive tract cancer is still H O n 2 2 2 1 n 0 n 1 n n 0 2 1 n 1 o ; , ve S unknown. A meta-analysis incorporating all available data ) it O a ; ) (% ) ) ) ) ) ) )2 ) ) ) ) )1 ) )4 ) ge leb from correlative studies is a reasonable method by which to +-(1L itsen .4914 .3663 .3828 .6124 .0056 .6036 .(634 .3924 .7405 .5454 .1654 .(174 .6744 .(155 .1284 ,:sn0 liaaav addressthesequestions.Weconductedthisstudyandfound t ( ( ( ( ( ( 6 ( ( ( ( 9 ( 2 ( a t D a 3 7 2 3 5 0 0 8 4 5 6 6 4 0 7 d no nearly 50% of gastrointestinal tract cancer patients showed P p 1 3 8 4 6 7 1 8 5 1 2 6 6 1 2 e , n e N positive expression of PD-L1. Furthermore, patients with if A d ; a a a a a a a a a a a s y in in in in in in in in in in in a tr positive expression of PD-L1 had significantly poorer surh h h h h h h h h h h w is c c c c c c c c c c c P m f f f f f f f f f f f P e vival than with those with negative expression. ilco lico lico lico lico lico lico lico ilco lico lico .gn tcho b b b b b b b b b b b ro is ItisnotablethatthePD-L1expressionratewasdelineated up up up up up up up up up up up ts ho tryn ayn ’lsree ’lsree ’lsree ’lsree a ’lsree ’lsree ’lsree ’lsree lraend ’lsree ’lsree ’lsree ,an3d inumm laepspslwiehde.nWsetriccotuerldcrsieteertihaaftosrtpuodsieitsivuesiPnDg-aLc1uet-xopfrfevssailounew.e5r0e uo apn rem epo epo epo epo reo epo epo epo epo itzw epo epo epo ;tae ,CH forH-score16,22,24,26,27showedalowerpositivePD-L1expresC Ja g P P P P K P P P P s P P P r I e ; d o o it sion rate than those using ,50.17,19,28,29 A similar result was m ra ) ) ) ) ) ) 5 6 ) ) ) ) ) ) .77 .53 .00 .57 .25 .36 .29 .40 .76 .66 .03 .50 ,;2 rad found if 10% was taken as the cut-off value when using 6 3 1 7 6 7 7 1 4 2 7 2 k z (7 (7 (6 (6 (2 (1 (6 (6 (3 (4 (4 (6 ae ah the percentage method. Since IHC evaluation methods and w , d e d a o l n w o d y p a r M n an an 76 75 61 75 15 15 72 an 35 67 61 87 35 , R ; ; cut-off values were not consistent for each gastrointestinal 1 H e a v $60 ()s% .)488 .)752 .)005 .)*450 #.)811 .)2446 .)947 .)163 .)258 .)1626 .)573 ,gaen0 iraccno twrahcetncsatnucdeirestywpee,resusbtrgartoifuiepdmbeytat-uamnaolrytsyispew.aWsneoctopuoldssaiblsloe it m (4 (6 (6 (5 (2 (8 (5 (6 (4 (4 (5 :sa itrc see that studies using a cut-off value .50 for H-score16,26,27 ge rae a a 8 4 5 6 3 2 2 a 6 a 9 1 0 s d a A y n n 4 6 6 5 5 1 6 n 3 n 6 1 3 e g in , showed a greater difference in OS between PD-L1 positive e h T trsndaage ,ittsaenP N 31 101 99 102 100 111 243 205 107 33 57 ,0142 143 185 56 Itsraeedwm l;raaccenCG saingdnnifeicgaantitvseugrvroivuaplsbtehnaenftihtsowseeuresionbgta,in5e0d,1i7n,19t,2h8eafltohromuegrhdnuoe T S e tolimitedsamplesizes.Moreover,theunfavorableprognoscnoO lssye laeu +)(1 ll.)scee sgaehpo tic value of PD-L1 was significantly seen in patients with a v L iv , esophageal cancer.16,17 Despite some trends observed, we ­an ff - its EC ta -o PD % % % % 0 % 0 0 o .e ;r currently cannot draw a valid conclusion that PD-L1 status e t 0 6 2 0 0 0 0 0 0 0 0 0 0 p v e u r 1 6 0 2 1 1 6 1 2 1 2 2 2 2 fo ita cn m C fo $ $ . n $ $ $ $ $ $ $ $ $ $ $ e g a is a predictor of prognosis for patients with gastric cancer a fro a tgan ­le1n ltacc orcolorectalcarcinoma.Consideringtheconsistenttrendof s e iteud itano tagen e e e tagen tagen e tagen e tagen e e e e (rcep i/vePD lrceoo the prognostic significance of PD-L1 when using different sedd ICH lvaeu rceeP ­srcho ­srcho an ­srcho rceeP rceeP ­srcho rceeP ­srcho rceeP ­srcho ­srcho ­srcho ­srcho ×)PP ­litsp1o ,;RCC kprinodvsenofinanantio-PthDer-Lm1eatan-taibnoaldyiseiss,t3o0ssutabignrtouumpoarncaelyllssehsaresgbaerednlcu itsyn rPD lrav n r e h te . ing source and type of antibody are not necessary. ifo uom ep c c c c c c itgn tsn icen iitsve itssc T ty ce ce ce gc gc gc gc gc gc rc rc rc rc rc rc iitann sreep ifend ­lp1o Limitations and future directions itre 005 2 103 i(ss brreh ,Icno ,)PD Efforts were made to conduct a comprehensive analysis raacchla1ebT ,tryyaeduS 15l,iitsaage2hhO61,lltsae1210oo 71,ltacee4210nh 81,ltae0062uW91,ltaggee2014n 02,ltae0412uho 12,litae0142Km22,liJtagae1402n 32,litage210n5Q24,ltaae0212uh 25,ltagae102nhZ 26,ltsrraeee2oD72,litsae1302h 28,llitagae210n4 92,ltaae4210hoZ a=­srceho:tseoN#.$./sragayee07 C:iitsrvaenbboA +­lli;(ag11n1PdD tttbroheoeiaaninctmskewsnptoaeincwratltlehotdefrgaPqecuDdte.c-sLaFtnii1orcsnestrta,ootffbuuasetlxlos,pnorwempeseascitoliaienmlnctuirtalapattretioeodgonnfsooPrsstDieisls-ltLiisnm1hogaautanelsdddOncoTargets andTherapy 2015:8 Figure 2 (Continued) submit your manuscript | www.dovepress.com Dovepress 2621 N 101 205 33 C Confidence interval 0.366 (0.278, 0.464) 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 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. Conclusion 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 esophageal cancer. Acknowledgment 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 paper. Disclosure The authors declare no conflicts of interest in this work. submit your manuscript | www.dovepress.com Dovepress .vdoep lsyeon om oF fr d e d a o l n w o d y p a r e h T d n a s t e g r a T o c n O Supplementary material Publish your work in this journal 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 1. Siegel R , Naishadham D , Jemal A . Cancer statistics, 2012 . CA Cancer J Clin. 2012 ; 62 ( 1 ): 10 - 29 . 2. Bjelakovic G , Nikolova D , Simonetti RG , Gluud C . Antioxidant supplements for preventing gastrointestinal cancers . Cochrane Database Syst Rev . 2008 ; (3):CD004183. 3. Yang S , Wu S , Huang Y , et al. Screening for oesophageal cancer . Cochrane Database Syst Rev . 2012 ; 12 : CD007883 . 4. Markman JL , Shiao SL . Impact of the immune system and immunotherapy in colorectal cancer . J Gastrointest Oncol . 2015 ; 6 ( 2 ): 208 - 223 . 5. Ferrone S , Whiteside TL . Tumor microenvironment and immune escape . Surg Oncol Clin N Am . 2007 ; 16 ( 4 ): 755 - 774 . 6. Korman AJ , Peggs KS , Allison JP . Checkpoint blockade in cancer immunotherapy . Adv Immunol . 2006 ; 90 : 297 - 339 . 7. McDermott DF , Atkins MB . PD-1 as a potential target in cancer therapy . Cancer Med . 2013 ; 2 ( 5 ): 662 - 673 . 8. Chen J , Li G , Meng H , et al. Upregulation of B7-H1 expression is associated with macrophage infiltration in hepatocellular carcinomas . Cancer Immunol Immunother . 2012 ; 61 ( 1 ): 101 - 108 . 9. Wang A , Wang HY , Liu Y , et al. The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis . Eur J Surg Oncol . 2015 ; 41 ( 4 ): 450 - 456 . 10. Zhou ZJ , Zhan P , Song Y. PD-L1 over -expression and survival in patients with non-small cell lung cancer: a meta-analysis . Transl Lung Cancer Res . 2015 ; 4 ( 2 ): 203 - 208 . 11. Pan ZK , Ye F , Wu X , An HX , Wu JX . Clinicopathological and prognostic significance of programmed cell death ligand1 (PD-L1) expression in patients with non-small cell lung cancer: a meta-analysis . J Thorac Dis . 2015 ; 7 ( 3 ): 462 - 470 . 12. Tierney JF , Stewart LA , Ghersi D , Burdett S , Sydes MR . Practical methods for incorporating summary time-to-event data into meta-analysis . Trials . 2007 ; 8 : 16 . 13. Wells GA , Shea B , O'Connell D , et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in metaanalyses [research tool] . Ottawa, ON: Ottawa Hospital Research Institute; 2014 . Available at: http://www.ohri.ca/programs/clinical_ epidemiology/oxford.htm. Accessed August 1 , 2015 . 14. Begg CB , Mazumdar M. Operating characteristics of a rank correlation test for publication bias . Biometrics . 1994 ; 50 ( 4 ): 1088 - 1101 . 15. Ohigashi Y , Sho M , Yamada Y , 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 ( 8 ): 2947 - 2953 . 16. Loos M , Langer R , Schuster T , et al. Clinical significance of the costimulatory molecule B7-H1 in Barrett carcinoma . Ann Thorac Surg . 2011 ; 91 ( 4 ): 1025 - 1031 . 17. Chen L , Deng H , Lu M , 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 . 18. Wu C , Zhu Y , Jiang J , et al. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance . Acta Histochem . 2006 ; 108 ( 1 ): 19 - 24 . 19. Geng Y , Wang H , Lu C , et al. Expression of costimulatory molecules B7-H1, B7-H4 and Foxp3+ Tregs in gastric cancer and its clinical significance . Int J Clin Oncol . 2014 ; 20 ( 2 ): 273 - 281 . 20. Hou J , Yu Z , Xiang R , 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 ( 3 ): 284 - 291 . 21. Kim JW , Nam KH , Ahn SH , et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer . Gastric Cancer . 2014 . Epub November 26. 22. Jiang D , Xu YY , Li F , Xu B , Zhang XG . The role of B7-H1 in gastric carcinoma: clinical significance and related mechanism . Med Oncol . 2014 ; 31 ( 11 ): 268 . 23. Qing Y , Li Q , Ren T , 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 . 24. Hua D , Sun J , Mao Y , Chen LJ , Wu YY , Zhang XG . B7-H1 expression is associated with expansion of regulatory T cells in colorectal carcinoma . World J Gastroenterol . 2012 ; 18 ( 9 ): 971 - 978 . 25. Zhang MY , Yang YY , Wang XH , Li XF. [ Expression of Bcl-2, PD-L1 and its clinical significance in colorectal cancer .] Sichuan Da Xue Xue Bao Yi Xue Ban . 2012 ; 43 ( 6 ): 827 - 829 , 859 . Chinese. 26. Droeser RA , Hirt C , Viehl CT , et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer . Eur J Cancer . 2013 ; 49 ( 9 ): 2233 - 2242 . 27. Shi SJ , Wang LJ , Wang GD , 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 ( 10 ): e76012 . 28. Liang M , Li J , Wang D , 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 . Tumor Biol . 2014 ; 35 ( 1 ): 55 - 60 . 29. Zhao LW , Li C , Zhang RL , et al. B7 -H1 and B7-H4 expression in colorectal carcinoma: correlation with tumor FOXP3(+) regulatory T-cell infiltration . Acta Histochem . 2014 ; 116 ( 7 ): 1163 - 1168 . 30. Zhang Y , Kang S , Shen J , et al. Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) Expression in epithelial-originated cancer: a meta-analysis . Medicine (Baltimore) . 2015 ; 94 ( 6 ): e515 . 31. Garon EB , Rizvi NA , Hui R , et al; KEYNOTE-001 Investigators . Pembrolizumab for the treatment of non-small-cell lung cancer . N Engl J Med . 2015 ; 372 ( 21 ): 2018 - 2028 .


This is a preview of a remote PDF: https://www.dovepress.com/getfile.php?fileID=27043

Baohua Huang, Lei Chen, Cuixia Bao, Chengming Sun, Jie Li, Lipeng Wang, Xia Zhang. 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, 2015, 2617-2625, DOI: 10.2147/OTT.S91025