Evaluation of Programmed Death Ligand-1 Immunohistochemical Expression and Tumor-Infiltrating Lymphocytes in Different Types of Endometrial Carcinoma

Authors

  • Ragaa A. Salem Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  • Laila M. Nabegh Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  • Riham M. Abu-Zeid Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  • Nermine M. Abd Raboh Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  • Mariam El-Rashedy Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt https://orcid.org/0000-0001-7235-7488

DOI:

https://doi.org/10.3889/oamjms.2022.9195

Keywords:

Endometrial carcinoma, Programmed death ligand-1, Tumor infiltrating lymphocytes, Tumor microenvironment

Abstract

BACKGROUND: Endometrial cancer (EC) identified at an early stage is successfully treated in a majority of patients with surgery with or without radiotherapy or chemotherapy. For patients with advanced disease, however, the prognosis is poor; 5-year survival rates are less than 50% in patients with lymph node metastases and less than 20% with peritoneal or distant metastases. Previous studies proved that programmed death-1/programmed death ligand-1 (PD1-/PD-L1) blockers are currently effectively used as immunotherapies in a number of tumors such as melanoma and non-small cell lung cancer.

AIM: This study was conducted to determine the expression of PD L1 in endometrial carcinoma and to assess its potential role as a biomarker for different types that can be used to screen candidates fit for immunotherapy.

MATERIALS AND METHODS: This cross-sectional study was carried out on 32 cases of endometrial carcinoma cases that underwent endometrial biopsies, dilatation, and curettage or radical hysterectomies at Ain Shams University Hospitals Pathology Units from 2018 to 2020 with their clinical and radiological assessments. Correlation between hematoxylin and eosin-stained histopathological sections and PD-L1 immunohistochemical staining of the same sections, mainly emphasizing the tumor-infiltrating lymphocytes, was done.

RESULTS: PDL-1-positive expression of both tumor cells and TILs was significantly more frequent in type II endometrial carcinoma (p = 0.04 and 0.03, respectively) using a cut-off value 10%, compared to type I. Moreover, Grade III tumors showed significantly more frequent PDL-1 expression in both tumor cells and TILs than Grade I and II tumors, using 5% and 10% cut-off values indicating that PDL-1 is overexpressed in aggressive tumors.

CONCLUSION: PD-L1 staining is significantly related to high-grade tumors and type II endometrial carcinomas, the aggressive types, which support their probable benefit from immunotherapy. Separate assessment of PD-L1-positive staining in both tumor cells or TILs with a cut-off value 10% can significantly reflect the aggressiveness of the tumor and its probable benefit from immunotherapy.

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References

Lax SF. Molecular genetic pathways in various types of endometrial carcinoma: From a phenotypical to a molecular-based classification. Virchows Arch. 2004;444(3):213-23. https://doi.org/10.1007/s00428-003-0947-3 PMid:14747944 DOI: https://doi.org/10.1007/s00428-003-0947-3

Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1(9):1319-23. https://doi.org/10.1001/jamaoncol.2015.2151 PMid:26181000 DOI: https://doi.org/10.1001/jamaoncol.2015.2151

Köhnke T, Krupka C, Tischer J, Knösel T, Subklewe M. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J Hematol Oncol. 2015;8(1):115. https://doi.org/10.1186/s13045-015-0213-6 PMid:26449653 DOI: https://doi.org/10.1186/s13045-015-0213-6

Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, et al. Expression of the B7-related molecule B7-H1 by glioma cells: A potential mechanism of immune paralysis. Cancer Res. 2003;63(21):7462-7. PMid:0008-5472

Xue S, Song G, Yu J. The prognostic significance of PD-L1 expression in patients with glioma: A meta-analysis. Sci Rep. 2017;7(1):4231. https://doi.org/10.1038/s41598-017-04023-x PMid:28652622 DOI: https://doi.org/10.1038/s41598-017-04023-x

Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev. 2014;23(12):2965-70. https://doi.org/10.1158/1055-9965.EPI-14-0654 PMid:25392179 DOI: https://doi.org/10.1158/1055-9965.EPI-14-0654

Guilleminault L, Lemarié E, Heuzé-Vourc’h N. Monoclonal antibodies: An emerging class of therapeutics in non-small cell lung cancer. J Cancer Ther. 2012;3(6):1170-90. https://doi.org/10.4236/jct.2012.36153 DOI: https://doi.org/10.4236/jct.2012.36153

Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33. https://doi.org/10.1056/NEJMoa1302369 PMid:23724867 DOI: https://doi.org/10.1056/NEJMoa1302369

Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015;17(8):1064-75. https://doi.org/10.1093/neuonc/nou307 PMid:25355681 DOI: https://doi.org/10.1093/neuonc/nou307

Tsai KK, Daud AI. Nivolumab plus ipilimumab in the treatment of advanced melanoma. J Hematol Oncol. 2015;8(1):1-4. https://doi.org/10.1186/s13045-015-0219-0 DOI: https://doi.org/10.1186/s13045-015-0219-0

Grigg C, Rizvi NA. PD-L1 biomarker testing for non-small cell lung cancer: Truth or fiction? J Immunother Cancer. 2016;4(1):48. https://doi.org/10.1186/s40425-016-0153-x PMid:27532023 DOI: https://doi.org/10.1186/s40425-016-0153-x

Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362(6411):3593. https://doi.org/10.1126/science.aar3593 PMid:30309915 DOI: https://doi.org/10.1126/science.aar3593

Maisel K, Merrilees MJ, Atochina-Vasserman EN, Lian L, Obraztsova K, Rue R, et al. Immune checkpoint ligand PD-L1 is upregulated in pulmonary lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 2018;59(6):723-32. https://doi.org/10.1165/rcmb.2018-0123OC PMid:30095976 DOI: https://doi.org/10.1165/rcmb.2018-0123OC

Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015;11(9):504-14. https://doi.org/10.1038/nrneurol.2015.139 PMid:26260659 DOI: https://doi.org/10.1038/nrneurol.2015.139

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-39. https://doi.org/10.1056/NEJMoa1507643 PMid:26412456 DOI: https://doi.org/10.1056/NEJMoa1507643

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-35. https://doi.org/10.1056/NEJMoa1504627 PMid:26028407 DOI: https://doi.org/10.1056/NEJMoa1504627

Zajac M, Ye J, Mukhopadhyay P, Jin X, Ben Y, Antal J, et al. Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy. PloS One. 2020;15(4):0231936. https://doi.org/10.1371/journal.pone.0231936 PMid:32339189 DOI: https://doi.org/10.1371/journal.pone.0231936

Kir G, Soylemez T, Olgun ZC, Aydin A, McCluggage WG. Correlation of PD-L1 expression with immunohistochemically determined molecular profile in endometrial carcinomas. Virchows Archiv. 2020;477(6):845-56. https://doi.1007/s00428-020-02867-9 PMid:32594230 DOI: https://doi.org/10.1007/s00428-020-02867-9

Zhang T, Liu Q, Zhu Y, Zhang S, Peng Q, Strickland AL, et al. PD-L1 expression in endometrial serous carcinoma and its prognostic significance. Cancer Manage Res. 2021;13:9157. https://doi.org/10.2147/CMAR.S337271 PMid:34934360 DOI: https://doi.org/10.2147/CMAR.S337271

Willis BC, Sloan EA, Atkins KA, Stoler MH, Mills AM. Mismatch repair status and PD-L1 expression in clear cell carcinomas of the ovary and endometrium. Modern Pathol. 2017;30(11):1622-32. https://doi.org/10.1038/modpathol.2017.67 PMid:28752845 DOI: https://doi.org/10.1038/modpathol.2017.67

Bregar A, Deshpande A, Grange C, Zi T, Stall J, Hirsch H, et al. Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors. Gynecol Oncol. 2017;145(3):446-52. https://doi.org/1016/j.ygyno.2017.03.006Get PMid:28347512 DOI: https://doi.org/10.1016/j.ygyno.2017.03.006

Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020;11(1):1-8. https://doi.org/10.1038/s41467-020-18570-x DOI: https://doi.org/10.1038/s41467-020-18570-x

Wang X, Gan L, Ye J, Tang M, Liu W. The value of immune-related genes signature in osteosarcoma based on weighted gene co-expression network analysis. J Immunol Res. 2021;2021:9989321. https://doi.org/10.1155/2021/9989321 DOI: https://doi.org/10.1155/2021/9989321

Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y, et al. PDL1 Regulation by p53 via miR-34. JNCI: J Natl Cancer Inst. 2016;108(1):303. https://doi.org/0.1093/jnci/djv303 PMid:26577528 DOI: https://doi.org/10.1093/jnci/djv303

Tojyo I, Shintani Y, Nakanishi T, Okamoto K, Hiraishi Y, Fujita S, et al. PD-L1 expression correlated with p53 expression in oral squamous cell carcinoma. Maxillofac Plast Reconstr Surg. 2019;41(1):56. https://doi.org/10.1186/s40902-019-0239-8 PMid:31857991 DOI: https://doi.org/10.1186/s40902-019-0239-8

Suda K, Rozeboom L, Rivard CJ, Yu H, Ellison K, Melnick MA, et al. Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells. Lung Cancer. 2017;109:1-8. https://doi.org/10.1016/j.lungcan.2017.04.010 PMid:28577937 DOI: https://doi.org/10.1016/j.lungcan.2017.04.010

Lu L, Li Y, Luo R, Xu J, Feng J, Wang M. Prognostic and clinicopathological role of PD-L1 in endometrial cancer: A meta-analysis. Front Oncol. 2020;10:632. https://doi.org/3389/fonc.2020.00632 PMid:32426281 DOI: https://doi.org/10.3389/fonc.2020.00632

Khalifa R, Elsese N, El-Desouky K, Shaair H, Helal D. Immune checkpoint proteins (PD-L1 and CTLA-4) in endometrial carcinoma: Prognostic role and correlation with CD4+/CD8+ tumor infiltrating lymphocytes (TILs) ratio. J Immunoassay Immunochem. 2021;43(2):192-212. https://doi.org/10.1080/153 21819.2021.1981377 PMid:34697997 DOI: https://doi.org/10.1080/15321819.2021.1981377

Al-Hussaini M, Lataifeh I, Jaradat I, Abdeen G, Otay L, Badran O, et al. Undifferentiated endometrial carcinoma, an immunohistochemical study including PD-L1 testing of a series of cases from a single cancer center. Int J Gynecol Pathol. 2018;37(6):564-74. https://doi.org/10.1097/PGP.0000000000000449 PMid:30059455 DOI: https://doi.org/10.1097/PGP.0000000000000449

Sloan EA, Ring KL, Willis BC, Modesitt SC, Mills AM. PD-L1 expression in mismatch repair-deficient endometrial carcinomas, including Lynch syndrome-associated and MLH1 promoter hypermethylated tumors. Am J Surg Pathol. 2017;41(3):326-33. https://doi.org/10.1097/PAS.0000000000000783 PMid:27984238 DOI: https://doi.org/10.1097/PAS.0000000000000783

Roper E, Lum T, Palme CE, Ashford B, Ch’ng S, Ranson M, et al. PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma. Pathology. 2017;49(5):499-505. https://doi.org/10.1016/j.pathol.2017.04.00 PMid:28666643 DOI: https://doi.org/10.1016/j.pathol.2017.04.004

O’Shaughnessy MJ, Murray KS, La Rosa SP, Budhu S, Merghoub T, Somma A, et al. Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors. Clin Cancer Res. 2018;24(3):592-9. https://doi.org/10.1158/1078-0432.CCR-17-0186 PMid:28954788 DOI: https://doi.org/10.1158/1078-0432.CCR-17-0186

Mwafy SE, Eid AM, El-Anwar N. Mismatch repair status in endometrioid type of endometrial carcinoma: Association with clinicopathological parameters. Int J Cancer Biomed Res. 2020;4(3):209-15. https://doi.org/10.21608/jcbr.2020.35282.1053 DOI: https://doi.org/10.21608/jcbr.2020.35282.1053

Ock CY, Keam B, Kim S, Lee JS, Kim M, Kim TM, et al. Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T-cell infiltration. Clin Cancer Res. 2016;22(9):2261-70. https://doi.org/10.1158/1078-0432.CCR-15-2834 PMid:26819449 DOI: https://doi.org/10.1158/1078-0432.CCR-15-2834

Pasanen A, Ahvenainen T, Pellinen T, Vahteristo P, Loukovaara M, Bützow R. PD-L1 expression in endometrial carcinoma cells and intratumoral immune cells: Differences across histologic and TCGA-based molecular subgroups. Am J Surg Pathol. 2020;44(2):174-81. https://doi.org/10.1097/PAS.0000000000001395 PMid:31651527 DOI: https://doi.org/10.1097/PAS.0000000000001395

Noh BJ, Kwak JY, Eom DW. Immune classification for the PD-L1 expression and tumour-infiltrating lymphocytes in colorectal adenocarcinoma. BMC Cancer. 2020;20(1):58. https://doi.org/10.1186/s12885-020-6553-9 PMid:31992245 DOI: https://doi.org/10.1186/s12885-020-6553-9

Oh SA, Wu DC, Cheung J, Navarro A, Xiong H, Cubas R, et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat Cancer. 2020;1(7):681-91. Htps://doi.org/10.1038/s43018-020-0075-x PMid:35122038 DOI: https://doi.org/10.1038/s43018-020-0075-x

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Published

2022-04-08

How to Cite

1.
Salem RA, Nabegh LM, Abu-Zeid RM, Abd Raboh NM, El-Rashedy M. Evaluation of Programmed Death Ligand-1 Immunohistochemical Expression and Tumor-Infiltrating Lymphocytes in Different Types of Endometrial Carcinoma. Open Access Maced J Med Sci [Internet]. 2022 Apr. 8 [cited 2024 Nov. 23];10(A):702-8. Available from: https://oamjms.eu/index.php/mjms/article/view/9195