The impact of programmed cell death-ligand 1 (PD-L1) and CD8 expression in grade 3 endometrial carcinomas

  • Stylianos VagiosEmail author
  • Petros Yiannou
  • Elpida Giannikaki
  • Triada Doulgeraki
  • Christos Papadimitriou
  • Alexandros Rodolakis
  • Afroditi Nonni
  • Athanassios Vlachos
  • Kitty Pavlakis
Original Article



To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters.


One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PD-L1 and CD8 + expression was evaluated by immunohistochemistry.


In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with non-endometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to non-endometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032).


In grade 3 endometrial carcinomas, both of endometrioid and non-endometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology.


PD-L1 CD8 Endometrial cancer 



This research work was supported by the Onassis Foundation—Scholarship ID: G ZO 001-1/2018-2019.

Compliance with ethical standards

Conflict of interest

Onassis Foundation did not influence on the decision to submit this manuscript or on its content. We declare that we have no conflict of interest.

Supplementary material

10147_2019_1484_MOESM1_ESM.docx (12 kb)
Supplementary file1 (DOCX 12 kb)


  1. 1.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. CrossRefGoogle Scholar
  2. 2.
    Miller KD, Siegel RL, Lin CC et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66(4):271–289. CrossRefGoogle Scholar
  3. 3.
    Bokhman JV (1983) Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 15(1):10–17CrossRefGoogle Scholar
  4. 4.
    Colombo N, Creutzberg C, Amant F et al (2016) ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol 27(1):16–41. CrossRefGoogle Scholar
  5. 5.
    Suarez AA, Felix AS, Cohn DE (2017) Bokhman redux: endometrial cancer "types" in the 21st century. Gynecol Oncol 144(2):243–249. CrossRefGoogle Scholar
  6. 6.
    Piulats JM, Guerra E, Gil-Martin M et al (2017) Molecular approaches for classifying endometrial carcinoma. Gynecol Oncol 145(1):200–207. CrossRefGoogle Scholar
  7. 7.
    Kondratiev S, Sabo E, Yakirevich E et al (2004) Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res 10(13):4450–4456. CrossRefGoogle Scholar
  8. 8.
    de Jong RA, Boerma A, Boezen HM et al (2012) Loss of HLA class I and mismatch repair protein expression in sporadic endometrioid endometrial carcinomas. Int J Cancer 131(8):1828–1836. CrossRefGoogle Scholar
  9. 9.
    Suemori T, Susumu N, Iwata T et al (2015) Intratumoral CD8+ lymphocyte infiltration as a prognostic factor and its relationship with cyclooxygenase 2 expression and microsatellite instability in endometrial cancer. Int J Gynecol Cancer 25(7):1165–1172. CrossRefGoogle Scholar
  10. 10.
    de Jong RA, Leffers N, Boezen HM et al (2009) Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol 114(1):105–110. CrossRefGoogle Scholar
  11. 11.
    Iurchenko NP, Glushchenko NM, Buchynska LG (2014) Comprehensive analysis of intratumoral lymphocytes and FOXP3 expression in tumor cells of endometrial cancer. Exp Oncol 36(4):262–266Google Scholar
  12. 12.
    Ladanyi A, Somlai B, Gilde K et al (2004) T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 10(2):521–530CrossRefGoogle Scholar
  13. 13.
    Gadducci A, Guerrieri ME (2017) Immune checkpoint inhibitors in gynecological cancers: update of literature and perspectives of clinical research. Anticancer Res 37(11):5955–5965. Google Scholar
  14. 14.
    Howitt BE, Shukla SA, Sholl LM et al (2015) 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 1(9):1319–1323. CrossRefGoogle Scholar
  15. 15.
    Vanderstraeten A, Luyten C, Verbist G et al (2014) Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy. Cancer Immunol Immunother 63(6):545–557. CrossRefGoogle Scholar
  16. 16.
    Jones NL, Xiu J, Chatterjee-Paer S et al (2017) Distinct molecular landscapes between endometrioid and nonendometrioid uterine carcinomas. Int J Cancer 140(6):1396–1404. CrossRefGoogle Scholar
  17. 17.
    Liu J, Liu Y, Wang W et al (2015) Expression of immune checkpoint molecules in endometrial carcinoma. Exp Ther Med 10(5):1947–1952. CrossRefGoogle Scholar
  18. 18.
    Asaka S, Yen TT, Wang TL et al (2019) T cell-inflamed phenotype and increased Foxp3 expression in infiltrating T-cells of mismatch-repair deficient endometrial cancers. Mod Pathol 32(4):576–584. CrossRefGoogle Scholar
  19. 19.
    Crumley S, Kurnit K, Hudgens C et al (2019) Identification of a subset of microsatellite-stable endometrial carcinoma with high PD-L1 and CD8+ lymphocytes. Mod Pathol 32(3):396–404. CrossRefGoogle Scholar
  20. 20.
    Li Z, Joehlin-Price AS, Rhoades J et al (2018) Programmed death ligand 1 expression among 700 consecutive endometrial cancers: strong association with mismatch repair protein deficiency. Int J Gynecol Cancer 28(1):59–68. CrossRefGoogle Scholar
  21. 21.
    Bregar A, Deshpande A, Grange C et al (2017) Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors. Gynecol Oncol 145(3):446–452. CrossRefGoogle Scholar
  22. 22.
    Sungu N, Yildirim M, Desdicioglu R et al (2018) Expression of immunomodulatory molecules PD-1, PD-L1, and PD-L2, and their relationship with clinicopathologic characteristics in endometrial cancer. Int J Gynecol Pathol. Google Scholar
  23. 23.
    Tawadros AIF, Khalafalla MMM (2018) Expression of programmed death-ligand 1 and hypoxia-inducible factor-1alpha proteins in endometrial carcinoma. J Cancer Res Ther 14(Supplement):S1063–S1069. CrossRefGoogle Scholar
  24. 24.
    Kim J, Kim S, Lee HS et al (2018) Prognostic implication of programmed cell death 1 protein and its ligand expressions in endometrial cancer. Gynecol Oncol 149(2):381–387. CrossRefGoogle Scholar
  25. 25.
    Yamashita H, Nakayama K, Ishikawa M et al (2018) Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget 9(5):5652–5664. CrossRefGoogle Scholar
  26. 26.
    Thallinger C, Fureder T, Preusser M et al (2018) Review of cancer treatment with immune checkpoint inhibitors: current concepts, expectations, limitations and pitfalls. Wien Klin Wochenschr 130(3–4):85–91. CrossRefGoogle Scholar
  27. 27.
    Mittica G, Ghisoni E, Giannone G et al (2017) Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget 8(52):90532–90544. CrossRefGoogle Scholar
  28. 28.
    US Food and Drug Administration (2017) FDA approves first cancer treatment for any solid tumor with a specific genetic feature. US Food and Drug Administration, Silver SpringGoogle Scholar
  29. 29.
    De Felice F, Marchetti C, Tombolini V et al (2019) Immune check-point in endometrial cancer. Int J Clin Oncol. Google Scholar
  30. 30.
    Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. CrossRefGoogle Scholar
  31. 31.
    Eggink FA, Van Gool IC, Leary A et al (2017) Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology 6(2):e1264565. CrossRefGoogle Scholar
  32. 32.
    Ott PA, Bang YJ, Berton-Rigaud D et al (2017) Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study. J Clin Oncol 35(22):2535–2541. CrossRefGoogle Scholar
  33. 33.
    Kraft S, Fernandez-Figueras MT, Richarz NA et al (2017) PDL1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression. J Am Acad Dermatol 77(3):534–542. CrossRefGoogle Scholar
  34. 34.
    Teng MW, Ngiow SF, Ribas A et al (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145. CrossRefGoogle Scholar
  35. 35.
    Husseinzadeh N, Husseinzadeh HD (2014) mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: a critical review. Gynecol Oncol 133(2):375–381. CrossRefGoogle Scholar
  36. 36.
    Vanneman M, Dranoff G (2012) Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 12(4):237–251. CrossRefGoogle Scholar
  37. 37.
    Santin AD, Bellone S, Buza N et al (2016) Regression of chemotherapy-resistant polymerase epsilon (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with nivolumab. Clin Cancer Res 22(23):5682–5687. CrossRefGoogle Scholar
  38. 38.
    Mehnert JM, Panda A, Zhong H et al (2016) Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J Clin Investig 126(6):2334–2340. CrossRefGoogle Scholar
  39. 39.
    Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028. CrossRefGoogle Scholar
  40. 40.
    Sabatier R, Finetti P, Mamessier E et al (2015) Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6(7):5449–5464. CrossRefGoogle Scholar
  41. 41.
    Tamura T, Ohira M, Tanaka H et al (2015) Programmed death-1 ligand-1 (PDL1) expression is associated with the prognosis of patients with stage II/III gastric cancer. Anticancer Res 35(10):5369–5376Google Scholar
  42. 42.
    Mo Z, Liu J, Zhang Q et al (2016) Expression of PD-1, PD-L1 and PD-L2 is associated with differentiation status and histological type of endometrial cancer. Oncol Lett 12(2):944–950. CrossRefGoogle Scholar
  43. 43.
    Bellone S, Bignotti E, Lonardi S et al (2017) Polymerase epsilon (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro. Gynecol Oncol 144(1):146–152. CrossRefGoogle Scholar
  44. 44.
    Fridman WH, Pages F, Sautes-Fridman C et al (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. CrossRefGoogle Scholar
  45. 45.
    Cermakova P, Melichar B, Tomsova M et al (2014) Prognostic significance of CD3+ tumor-infiltrating lymphocytes in patients with endometrial carcinoma. Anticancer Res 34(10):5555–5561Google Scholar
  46. 46.
    Hendry S, Salgado R, Gevaert T et al (2017) Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immuno-oncology biomarkers working group: part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anat Pathol 24(5):235–251. CrossRefGoogle Scholar
  47. 47.
    Thompson ED, Zahurak M, Murphy A et al (2017) Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut 66(5):794–801. CrossRefGoogle Scholar
  48. 48.
    Al-Shibli KI, Donnem T, Al-Saad S et al (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14(16):5220–5227. CrossRefGoogle Scholar
  49. 49.
    Hendry S, Salgado R, Gevaert T et al (2017) Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immuno-oncology biomarkers working group: part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv Anat Pathol 24(6):311–335. CrossRefGoogle Scholar
  50. 50.
    Jung IK, Kim SS, Suh DS et al (2014) Tumor-infiltration of T-lymphocytes is inversely correlated with clinicopathologic factors in endometrial adenocarcinoma. Obstet Gynecol Sci 57(4):266–273. CrossRefGoogle Scholar
  51. 51.
    Wang Q, Lou W, Di W et al (2017) Prognostic value of tumor PD-L1 expression combined with CD8(+) tumor infiltrating lymphocytes in high grade serous ovarian cancer. Int Immunopharmacol 52:7–14. CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Stylianos Vagios
    • 1
    Email author
  • Petros Yiannou
    • 2
  • Elpida Giannikaki
    • 3
  • Triada Doulgeraki
    • 2
  • Christos Papadimitriou
    • 4
  • Alexandros Rodolakis
    • 5
  • Afroditi Nonni
    • 1
  • Athanassios Vlachos
    • 6
  • Kitty Pavlakis
    • 1
    • 2
  1. 1.Pathology DepartmentNational and Kapodistrian University of AthensAthensGreece
  2. 2.Pathology Department“IASO” Women’s HospitalAthensGreece
  3. 3.Pathology DepartmentVenizeleio-Pananeio General HospitalHeraklionGreece
  4. 4.Oncology Unit, 2nd Department of Surgery, Aretaieion HospitalNational and Kapodistrian University of AthensAthensGreece
  5. 5.1st Department of Obstetrics and Gynecology, Alexandra HospitalNational and Kapodistrian University of AthensAthensGreece
  6. 6.Department of Gynecological Oncology“IASO” Women’s HospitalAthensGreece

Personalised recommendations