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Open Access 01-12-2018 | Research

PD-L1 in pancreatic ductal adenocarcinoma: a retrospective analysis of 373 Chinese patients using an in vitro diagnostic assay

Authors: Xiaolong Liang, Jian Sun, Huanwen Wu, Yufeng Luo, Lili Wang, Junliang Lu, Zhiwen Zhang, Junchao Guo, Zhiyong Liang, Tonghua Liu

Published in: Diagnostic Pathology | Issue 1/2018

Abstract

Background

Programmed death ligand 1 (PD-L1) has shown potential as a therapeutic target in numerous solid tumors. Its prognostic significance has also been established in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to explore PD-L1 expression in PDAC cases in a large Chinese cohort using an in vitro diagnostic (IVD) assay to provide further insight into the potential value of programmed cell death protein 1 (PD-1) as a therapeutic target.

Methods

Three hundred seventy-three PDAC patients were retrospectively recruited in this study. Tissue microarray (TMA) blocks were made from available formalin-fixed and paraffin-embedded (FFPE) tumor and matched adjacent tissue specimens. We evaluated PD-L1 protein expression via immunohistochemistry (IHC) using a U.S. Food and Drug Administration (FDA)-approved IVD assay. The relationships between PD-L1 positivity and both clinicopathological characteristics and patient prognosis were analyzed. PD-1 expression and clinicopathological significance were also evaluated.

Results

PD-L1 and PD-1 positivity were observed in 3.2% and 7.5% of cases, respectively. PD-L1 showed a predominantly membranous pattern in tumor cells, while no positive PD-L1 staining was observed in normal regions. Statistical analyses revealed that PD-L1 expression was associated with lymph node metastasis. PD-L1 positivity was a prognostic indicator of progression-free survival (PFS) and overall survival (OS) in univariate analyses, but only PFS remained statistically significant in multivariate analysis. PD-1 expression was detected in lymphocytes and was not associated with any clinicopathological feature except a history of pancreatitis.

Conclusions

The PD-L1 positivity rate is low in PDAC when evaluated using a companion diagnostic assay. It remains an independent prognostic factor for poor PFS.

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Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL, Firpo MA, Mulvihill SJ. Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 2010;39(4):425–35. https://doi.org/10.1097/MPA.0b013e3181c15963.CrossRefPubMedPubMedCentral

Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375(18):1767–78. https://doi.org/10.1056/NEJMra1514296.CrossRefPubMedPubMedCentral

Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu L, Yao S, Anders RA, Laheru D, Wolfgang CL, Edil BH, Schulick RD, Jaffee EM, Zheng L. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T cell infiltration into pancreatic tumors. Journal of immunotherapy (Hagerstown, Md : 1997). 2015;38(1):1–11. https://doi.org/10.1097/cji.0000000000000062.

Wang X, Bao Z, Zhang X, Li F, Lai T, Cao C, Chen Z, Li W, Shen H, Ying S. Effectiveness and safety of PD-1/PD-L1 inhibitors in the treatment of solid tumors: a systematic review and meta-analysis. Oncotarget. 2017; https://doi.org/10.18632/oncotarget.18316.

Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu L, Yao S, Anders RA, Laheru D, Wolfgang CL, Edil BH, Schulick RD, Jaffee EM, Zheng L. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. Journal of immunotherapy (Hagerstown, Md : 1997). 2015;38(1):1–11. https://doi.org/10.1097/cji.0000000000000062.

Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, Vonderheide RH. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer immunology research. 2015;3(4):399–411. https://doi.org/10.1158/2326-6066.cir-14-0215.CrossRefPubMedPubMedCentral

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. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(7):2151–7. https://doi.org/10.1158/1078-0432.CCR-06-2746.CrossRef

Geng L, Huang D, Liu J, Qian Y, Deng J, Li D, Hu Z, Zhang J, Jiang G, Zheng S. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. J Cancer Res Clin Oncol. 2008;134(9):1021–7. https://doi.org/10.1007/s00432-008-0364-8.CrossRefPubMed

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. Ai zheng = Aizheng = Chinese journal of cancer. 2009;28(12):1328–32.CrossRefPubMed

10.

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(5):1059–65. https://doi.org/10.1007/s00268-010-0448-x.CrossRefPubMed

11.

Diana A, Wang LM, D'Costa Z, Allen P, Azad A, Silva MA, Soonawalla Z, Liu S, McKenna WG, Muschel RJ, Fokas E. Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget. 2016;7(27):40992–1004. https://doi.org/10.18632/oncotarget.10038.CrossRefPubMedPubMedCentral

12.

Wang Y, Lin J, Cui J, Han T, Jiao F, Meng Z, Wang L. Prognostic value and clinicopathological features of PD-1/PD-L1 expression with mismatch repair status and desmoplastic stroma in Chinese patients with pancreatic cancer. Oncotarget. 2017;8(6):9354–65. https://doi.org/10.18632/oncotarget.14069.PubMed

13.

Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, Oberlies NH, Pearce C, Liu K. The MLL1-H3K4me3 Axis-mediated PD-L1 expression and pancreatic cancer immune evasion. JNCI: journal of the National Cancer Institute 109 (6):djw283-djw283. 2017; https://doi.org/10.1093/jnci/djw283.

14.

Bosman FCF, Hruban RH. WHO classification of tumours of the digestive system. Lyon, France: IARC Press; 2010.

15.

Edge SB, Compton CC. The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4. https://doi.org/10.1245/s10434-010-0985-4.CrossRefPubMed

16.

Powles T, O'Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncology. 2017;3(9):e172411. https://doi.org/10.1001/jamaoncol.2017.2411.CrossRefPubMed

17.

Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, Ma Y, Zhao H, Huang Y, Xue C, Huang P, Hu Z, Zhao Y, Zhang L. Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Medical oncology (Northwood, London, England). 2015;32(3):86. https://doi.org/10.1007/s12032-015-0501-6.CrossRef

18.

Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett. 2009;279(1):1–7. https://doi.org/10.1016/j.canlet.2008.09.037.CrossRefPubMed

19.

Lutz ER, AA W, Bigelow E, Sharma R, Mo G, Soares K, Solt S, Dorman A, Wamwea A, Yager A, Laheru D, Wolfgang CL, Wang J, Hruban RH, Anders RA, Jaffee EM, Zheng L. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer immunology research. 2014;2(7):616–31. https://doi.org/10.1158/2326-6066.cir-14-0027.CrossRefPubMedPubMedCentral

20.

Igawa S, Sato Y, Ryuge S, Ichinoe M, Katono K, Hiyoshi Y, Otani S, Nagashio R, Nakashima H, Katagiri M, Sasaki J, Murakumo Y, Satoh Y, Masuda N. Impact of PD-L1 expression in patients with surgically resected non-small-cell lung cancer. Oncology. 2017; https://doi.org/10.1159/000458412.

21.

Botti G, Collina F, Scognamiglio G, Rao F, Peluso V, De Cecio R, Piezzo M, Landi G, De Laurentiis M, Cantile M, Di Bonito M. Programmed death ligand 1 (PD-L1) tumor expression is associated with a better prognosis and diabetic disease in triple negative breast cancer patients. Int J Mol Sci. 2017;18(2) https://doi.org/10.3390/ijms18020459.

22.

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, Azuma M, Nakajima Y. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;11(8):2947–53. https://doi.org/10.1158/1078-0432.CCR-04-1469.CrossRef

23.

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF. Investigators K- (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 376(11):1015–26. https://doi.org/10.1056/NEJMoa1613683.

24.

Abdul Karim L, Wang P, Chahine J, Kallakury B. PD-L1 IHC assays in melanoma. Histopathology. 2017; https://doi.org/10.1111/his.13174.

25.

Giraldo NA, Becht E, Vano Y, Petitprez F, Lacroix L, Validire P, Sanchez-Salas R, Ingels A, Oudard SM, Moatti A, Buttard B, Bourras S, Germain C, Cathelineau X, Fridman WH, Sautes-Fridman C. Tumor-infiltrating and peripheral blood T cell Immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017; https://doi.org/10.1158/1078-0432.CCR-16-2848.

26.

Dill EA, Gru AA, Atkins KA, Friedman LA, Moore ME, Bullock TN, Cross JV, Dillon PM, Mills AM. PD-L1 expression and Intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am J Surg Pathol. 2017;41(3):334–42. https://doi.org/10.1097/pas.0000000000000780.CrossRefPubMed

27.

Casadevall D, Clave S, Taus A, Hardy-Werbin M, Rocha P, Lorenzo M, Menendez S, Salido M, Albanell J, Pijuan L, Arriola E. Heterogeneity of tumor and immune cell PD-L1 expression and lymphocyte counts in surgical NSCLC samples. Clinical lung cancer. 2017; https://doi.org/10.1016/j.cllc.2017.04.014.

Title: PD-L1 in pancreatic ductal adenocarcinoma: a retrospective analysis of 373 Chinese patients using an in vitro diagnostic assay
Authors: Xiaolong Liang
Jian Sun
Huanwen Wu
Yufeng Luo
Lili Wang
Junliang Lu
Zhiwen Zhang
Junchao Guo
Zhiyong Liang
Tonghua Liu
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Diagnostic Pathology / Issue 1/2018
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/s13000-017-0678-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

PD-L1 in pancreatic ductal adenocarcinoma: a retrospective analysis of 373 Chinese patients using an in vitro diagnostic assay

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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