Tumoral and Stromal Pdl1 and Pdl2 Checkpoints Immunohistochemical Expression in Pancreatic Ductal Adenocarcinoma, a Promising Field Of Study

Authors

  • Lubna O. Abdel-Salam Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
  • Hala El Hanbuli Department of Pathology, Faculty of Medicine, Fayoum University, Egypt Keman Fares, Fayoum Governorate, Cairo, Egypt https://orcid.org/0000-0003-4147-1397
  • Dalia Nabil Abdelhafez Department of Pathology, Faculty of Medicine, Fayoum University, Cairo, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.9070

Keywords:

Pancreatic ductal adenocarcinoma, PDL1, PDL2

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is world-widely considered as one of the most malignant tumors. Programmed cell death protein 1 (PD-1), via its ligands PDL1 and PDL2 plays a critical role in cancer immunoediting. The ligands are expressed in many solid tumors and there is an emerging hope of using anti-PDL in cancer immunotherapy.

 

Material and methods:

This study included 40 patients with PDAC who underwent pancreaticoduodenectomy. PDL1 and PDL2 pancreatic expression were evaluated in these patients using immunohistochemical staining and correlated their expression levels with each patient’s reported clinicopathological features.

 

Results:

There were significant relations between high tumoral PDL1 expression and the PDAC tumor histologic grade (p= 0.021) and the tumor status (T) (p= 0.022), while the stromal expression of PDL1 showed non-significant relation with any of the studied features. There were significant relations between high tumoral PDL2 expression and tumor stage (p=0.012), while the stromal expression of PDL2 showed significant relation with tumor status, lymph node status, tumor stage and the presence lympho-vascular invasion with P value equal 0.001, 0.009, 0.009, 0.045 respectively.

Conclusion:

This study showed that in PDAC patients high tumoral PDL1 and PDL2 expression was associated with some important prognostic factors, while only stromal PDL2 expression was significantly associated with most of the studied prognostic features emphasizing a role of both markers in the prognosis of this neoplasm.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. https://doi.org/10.3322/caac.21442 DOI: https://doi.org/10.3322/caac.21442

Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World J Oncol. 2019;10:10-27. https://doi.org/10.14740/wjon1166 PMid:30834048 DOI: https://doi.org/10.14740/wjon1166

Saka D, Gökalp M, Piyade B, Cevik NC, Arik Sever E, Unutmaz D, et al. Mechanisms of T-cell exhaustion in pancreatic cancer. Cancers. 2020;12(8):2274. https://doi.org/10.3390/cancers12082274 PMid:32823814 DOI: https://doi.org/10.3390/cancers12082274

Melstrom LG, Salazar MD, Diamond DJ. The pancreatic cancer microenvironment: A true double agent. J Surg Oncol. 2017;116(1):7-15. https://doi.org/10.1002/jso.24643 PMid: 28605029 DOI: https://doi.org/10.1002/jso.24643

Torphy RJ, Zhu Y, Schulick RD. Immunotherapy for pancreatic cancer: Barriers and breakthroughs. Ann Gastroenterol Surg. 2018;2(4):274-81. https://doi.org/10.1002/ags3.12176 PMid:30003190 DOI: https://doi.org/10.1002/ags3.12176

Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47-52. https://doi.org/10.1038/nature16965 PMid:26909576 DOI: https://doi.org/10.1038/nature16965

Jamieson NB, Maker AV. Gene-expression profiling to predict responsiveness to immunotherapy. Cancer Gene Ther. 2017;24(3):134-40. https://doi.org/10.1038/cgt.2016.63 PMid:27834354 DOI: https://doi.org/10.1038/cgt.2016.63

Xiao G, Deng A, Liu H, Ge G, Liu X. Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1. Proc Natl Acad Sci USA. 2012;109(38):15419-24. https://doi.org/10.1073/pnas.1206370109 PMid:22949674 DOI: https://doi.org/10.1073/pnas.1206370109

Herzberg B, Campo MJ, Gainor JF. Immune checkpoint inhibitors in non-small cell lung cancer. Oncologist. 2017;22:81-88. https://doi.org/10.1634/theoncologist.2016-0189 PMid:27534574 DOI: https://doi.org/10.1634/theoncologist.2016-0189

Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255-65. https://doi.org/10.1016/S0140-6736(16)32517-X PMid:27979383 DOI: https://doi.org/10.1016/S0140-6736(16)32517-X

Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76. https://doi.org/10.1016/ S0140-6736(16)32455-2 PMid:27939400 DOI: https://doi.org/10.1016/S0140-6736(16)32455-2

Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. https://doi.org/10.1146/annurev.immunol.26.021607.090331 PMid:18173375 DOI: https://doi.org/10.1146/annurev.immunol.26.021607.090331

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64. https://doi.org/10.1038/nrc3239 PMid:22437870 DOI: https://doi.org/10.1038/nrc3239

Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8. https://doi.org/10.1038/85330 PMid:11224527 DOI: https://doi.org/10.1038/85330

Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24-33. https://doi.org/10.1016/j.molmed.2014.10.009 PMid:25440090 DOI: https://doi.org/10.1016/j.molmed.2014.10.009

Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor CD28 is a primary target for PD-1- mediated inhibition. Science. 2017;355(6332):1428-33. https://doi.org/10.1126/science.aaf1292 PMid:28280247 DOI: https://doi.org/10.1126/science.aaf1292

Rahn S, Kruger S, Mennrich R, Goebel L, Wesch D, Oberg HH, et al. POLE Score: A comprehensive profiling of programmed death 1 ligand 1 expression in pancreatic ductal adenocarcinoma. Oncotarget. 2019;10(16):1572-88. https://doi.org/10.18632/oncotarget.26705 PMid:30899426 DOI: https://doi.org/10.18632/oncotarget.26705

Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486-499. https://doi.org/10.1038/nri3862 PMid:26205583 DOI: https://doi.org/10.1038/nri3862

Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol. 2011;350:17-37. https://doi.org/10.1007/82_2010_116 PMid:21061197 DOI: https://doi.org/10.1007/82_2010_116

Feng M, Xiong G, Cao Z, Yang G, Zheng S, Song X, et al. PD-1/ PD-L1 and immunotherapy for pancreatic cancer. Cancer Lett. 2017;407:57-65. https://doi.org/10.1016/j.canlet.2017.08.006 PMid:28826722 DOI: https://doi.org/10.1016/j.canlet.2017.08.006

Takamori S, Takada K, Tagawa T, Toyokawa G, Hirai F, Yamashita N, et al. Differences in PD-L1 expression on tumor and immune cells between lung metastases and corresponding primary tumors. Surg Oncol. 2018;27(4):637-641. https://doi.org/10.1016/j.suronc.2018.08.001 PMid:30449485 DOI: https://doi.org/10.1016/j.suronc.2018.08.001

Hou Y, Nitta H, Wei L, Banks PM, Lustberg M, Wesolowski R, et al. PD-L1 expression and CD8-positive T cells are associated with favorable survival in HER2-positive invasive breast cancer. Breast J. 2018;24(6):911-9. https://doi.org/10.1111/tbj.13112 PMid:30230111 DOI: https://doi.org/10.1111/tbj.13112

Kollmann D, Ignatova D, Jedamzik J, Chang YT, Jomrich G, Baierl A, et al. PD-L1 expression is an independent predictor of favorable outcome in patients with localized esophageal adenocarcinoma. Oncoimmunology. 2018;13;7(6):e1435226. https://doi.org/10.1080/2162402X.2018.1435226 PMid:29872575 DOI: https://doi.org/10.1080/2162402X.2018.1435226

Yamaki S, Yanagimoto H, Tsuta K, Ryotal H, Kon M. PD-L1 expression in pancreatic ductal adenocarcinoma is a poor prognostic factor in patients with high CD8+ tumor-infiltrating lymphocytes: Highly sensitive detection using phosphor-integrated dot staining. Int J Clin Oncol. 2017;22(1):726-33. https://doi.org/10.1007/s10147-017-1112-3 PMid:28314962 DOI: https://doi.org/10.1007/s10147-017-1112-3

Huang Y, Zhang SD, McCrudden C, Chan KW, Lin Y, Kwok HF. The prognostic significance of PD-L1 in bladder cancer. Oncol Rep. 2015;33(6):3075-84. https://doi.org/10.3892/or.2015.3933 PMid:25963805 DOI: https://doi.org/10.3892/or.2015.3933

Ying L, Yan F, Meng Q, Yu L, Yuan X, Gantier MP, et al. PD-L1 expression is a prognostic factor in subgroups of gastric cancer patients stratified according to their levels of CD8 and FOXP3 immune markers. Oncoimmunology. 2018;7(6):e1433520. https://doi.org/10.1080/2162402X.2018.1433520 PMid:29872566 DOI: https://doi.org/10.1080/2162402X.2018.1433520

Iacovelli R, Nolè F, Verri E, Renne G, Paglino C, Santoni M, et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis. Target Oncol. 2016;11(2):143-8. https://doi.org/10.1007/s11523-015-0392-7 PMid:26429561 DOI: https://doi.org/10.1007/s11523-015-0392-7

Zhu J, Wen H, Bi R, Wu Y, Wu X. Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma. J Gynecol Oncol. 2017;28(6):e77. https://doi.org/10.3802/jgo.2017.28.e77 PMid:29027395 DOI: https://doi.org/10.3802/jgo.2017.28.e77

Knol AC, Nguyen JM, Pandolfino MC, Denis MG, Khammari A, Dréno B. PD-L1 expression by tumor cell lines: A predictive marker in melanoma. Exp Dermatol. 2018;27(6):647-655. https://doi.org/10.1111/exd.13526 PMid:29505109 DOI: https://doi.org/10.1111/exd.13526

Gagliano N, Sommariva M. PD-1/PD-L1 blockade: A new promising therapy for the treatment of pancreatic cancer? Pancreas Open J. 2018;2(1):e5-7. https://doi.org/10.17140/ POJ-2-e007 DOI: https://doi.org/10.17140/POJ-2-e007

Soares KC, Rucki AA, Kim V, Foley K, Solt, S, Wolfgang CL, et al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget. 2015;6(40):43005-15. https://doi.org/10.18632/oncotarget.5656 PMid:26515728 DOI: https://doi.org/10.18632/oncotarget.5656

Hruban RH, Adsay NV, Esposito I, Fukushima N, Furukawa T, Kloppel G, et al. Pancreatic ductal adenocarcinoma. In: WHO Classification of Tumours Editorial Board, editor. WHO Classification of Tumours: Digestive System Tumours. 5th ed. Lyon, France: International Agency for Research on Cancer; 2019. p. 322-32.

Kakar S, Pawlik TM, Allen PJ. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer-Verlag; 2017.

Ahn S, Lee Y, Kim JW, Lee JC, Hwang JH, Yoon YS, et al. Programmed cell death ligand-1 (PD-L1) expression in extrahepatic biliary tract cancers: A comparative study using 22C3, SP263 and E1L3N anti-PD-L1 antibodies. Histopathology. 2019;75(4):526-36. https://doi.org/10.1111/his.13901 PMid:31081949 DOI: https://doi.org/10.1111/his.13901

Tanigawa M, Naito Y, Akiba J, Kawahara A, Okabe Y, Ishida Y, et al. PD-L1 expression in pancreatic adenosquamous carcinoma: PD-L1 expression is limited to the squamous component. Pathol Res Pract. 2018;214(12):2069-74. https://doi.org/10.1016/j.prp.2018.10.006 PMid:30477643 DOI: https://doi.org/10.1016/j.prp.2018.10.006

Zhang Y, Xu J, Hua J, Liu J, Liang C, Meng Q, et al. A PD-L2-based immune marker signature helps to predict survival in resected pancreatic ductal adenocarcinoma. J Immunother Cancer. 2019;7(1):233. https://doi.org/10.1186/s40425-019-0703-0 PMid:31464648 DOI: https://doi.org/10.1186/s40425-019-0703-0

Pu N, Zhao G, Gao S, Cui Y, Xu Y, Lv Y, et al. Neutralizing TGF-β _promotes anti-tumor immunity of dendritic cells against pancreatic cancer by regulating T lymphocytes. Cent Eur J Immunol 2018;43(2):123-31. https://doi.org/10.5114/ceji.2018.77381 PMid:30135623 DOI: https://doi.org/10.5114/ceji.2018.77381

Xia B, Herbst RS. Immune checkpoint therapy for non-small-cell lung cancer: An update. Immunotherapy. 2016;8(3):279-98. https://doi.org/10.2217/imt.15.123 PMid:26860624 DOI: https://doi.org/10.2217/imt.15.123

Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: A novel role of pro-survival signalling in cancer. Ann Oncol. 2016;27(3):409-16. https://doi.org/10.1093/annonc/mdv615 PMid:26681673 DOI: https://doi.org/10.1093/annonc/mdv615

Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201-17. https://doi.org/10.1084/jem.20112741 PMid:22641383 DOI: https://doi.org/10.1084/jem.20112741

Gibbons Johnson RM, Dong H. Functional expression of programmed death-ligand 1 (B7-H1) by immune cells and tumor cells. Front Immunol. 2017;8:961. https://doi.org/10.3389/ fimmu.2017.00961 PMid:28848559 DOI: https://doi.org/10.3389/fimmu.2017.00961

Foley K, Kim V, Jaffee E, Zheng L. Current progress in immunotherapy for pancreatic cancer. Cancer Lett. 2016;381(1):244-51. https://doi.org/10.1016/j.canlet.2015.12.020 PMid:26723878 DOI: https://doi.org/10.1016/j.canlet.2015.12.020

Pu N, Lou W, Yu J. PD-1 immunotherapy in pancreatic cancer: Current status. J Pancreatol. 2019;2(1):6-10. https://doi.org/10.1097/JP9.0000000000000010 DOI: https://doi.org/10.1097/JP9.0000000000000010

Diana A, Wang LM, D’Costa Z, Allen P, Azad A, Silva MA, et al. 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 PMid:27329602 DOI: https://doi.org/10.18632/oncotarget.10038

Zhuan-Sun Y, Huang F, Feng M, Zhao X, Chen W, Zhu Z, et al. Prognostic value of PD-L1 overexpression for pancreatic cancer: evidence from a meta-analysis. Onco Targets Ther. 2017;10:5005-5012. https://doi.org/10.2147/OTT.S146383 PMid:29081663 DOI: https://doi.org/10.2147/OTT.S146383

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 DOI: https://doi.org/10.1007/s00268-010-0448-x

Fukuda T, Kamai T, Masuda A, Nukui A, Abe H, Arai K, et al. Higher preoperative serum levels of PD-L1 and B7-H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF-targeted therapy and unfavorable prognosis of renal cell carcinoma. Cancer Med. 2016;5(8):1810-20. https://doi.org/10.1002/cam4.754 PMid:27292320 DOI: https://doi.org/10.1002/cam4.754

Niemeijer AN, Sahba S, Smit EF, Lissenberg-Witte BI, de Langen AJ, Thunnissen E. Association of tumour and stroma PD-1, PD-L1, CD3, CD4 and CD8 expression with DCB and OS to nivolumab treatment in NSCLC patients pre-treated with chemotherapy. Br J Cancer. 2020;123(3):392-402. https://doi.org/10.1038/s41416-020-0888-5 PMid:32433601 DOI: https://doi.org/10.1038/s41416-020-0888-5

Miyoshi H, Kiyasu J, Kato T, Yoshida N, Shimono J, Yokoyama S, et al. PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma. Blood. 2016;128(10):1374-81. https://doi.org/10.1182/blood-2016-02-698936 PMid:27418641 DOI: https://doi.org/10.1182/blood-2016-02-698936

Zhai Q, Fan J, Lin Q, Liu X, Li J, Hong R, et al. Tumor stromal type is associated with stromal PD-L1 expression and predicts outcomes in breast cancer. PLoS One. 2019;14(10):e0223325. https://doi.org/10.1371/journal.pone.0223325 PMid:31584964 DOI: https://doi.org/10.1371/journal.pone.0223325

Wyss J, Dislich B, Koelzer VH, Galván JA, Dawson H, Hädrich M, et al. Stromal PD-1/PD-L1 expression predicts outcome in colon cancer patients. Clin Colorectal Cancer. 2019;18(1):e20-38. https://doi.org/10.1016/j.clcc.2018.09.007 PMid:30389315 DOI: https://doi.org/10.1016/j.clcc.2018.09.007

Kitano Y, Yamashita YI, Nakao Y, Itoyama R, Yusa T, Umezaki N, et al. Clinical significance of PD-L1 expression in both cancer and stroma cells of cholangiocarcinoma patients. Ann Surg Oncol. 2020;27(2):599-607. https://doi.org/10.1245/s10434-019-07701-4 PMid:31407173 DOI: https://doi.org/10.1245/s10434-019-07701-4

Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol. 2012;2012:656340. https://doi.org/10.1155/2012/656340 PMid:22611421 DOI: https://doi.org/10.1155/2012/656340

Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. PD-L2 expression in human tumors: Relevance to anti-PD-1 therapy in cancer. Clin Cancer Res. 2017;15;23(12):3158-67. https://doi.org/10.1158/1078-0432.CCR-16-1761 PMid:28619999 DOI: https://doi.org/10.1158/1078-0432.CCR-16-1761

Solinas C, Aiello M, Rozali E, Lambertini M, Willard-Gallo K, Migliori E. Programmed cell death-ligand 2: A neglected but important target in the immune response to cancer? Transl Oncol. 2020;13(10):100811. https://doi.org/10.1016/j.tranon.2020.100811 DOI: https://doi.org/10.1016/j.tranon.2020.100811

Nazareth MR, Broderick L, Simpson-Abelson MR, Kelleher RJ Jr., Yokota SJ, Bankert RB. Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J Immunol. 2007;178(9):5552-62. https://doi.org/10.4049/jimmunol.178.9.5552 DOI: https://doi.org/10.4049/jimmunol.178.9.5552

Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280-8. https://doi.org/10.1038/leu.2013.355 PMid: 24270737 DOI: https://doi.org/10.1038/leu.2013.355

Yang H, Zhou X, Sun L, Mao Y. Correlation between PD-L2 expression and clinical outcome in solid cancer patients: A meta-analysis. Front Oncol. 2019;9:47. https://doi.org/10.3389/fonc.2019.00047 PMid:30891423 DOI: https://doi.org/10.3389/fonc.2019.00047

Downloads

Published

2022-03-28

How to Cite

1.
Abdel-Salam LO, El Hanbuli H, Abdelhafez DN. Tumoral and Stromal Pdl1 and Pdl2 Checkpoints Immunohistochemical Expression in Pancreatic Ductal Adenocarcinoma, a Promising Field Of Study. Open Access Maced J Med Sci [Internet]. 2022 Mar. 28 [cited 2024 Nov. 21];10(A):775-81. Available from: https://oamjms.eu/index.php/mjms/article/view/9070