Vol 92, No 5 (2021)
Research paper
Published online: 2021-04-19

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The relation of CD3, CD4, CD8 and PD-1 expression with tumor type and prognosis in epithelial ovarian cancers

Yeliz Arman Karakaya1, Ayhan Atıgan2, Ömer Tolga Güler2, Atike Gökçen Demiray3, Ferda Bir2
Pubmed: 33914317
Ginekol Pol 2021;92(5):344-351.


Objectives: Ovarian cancer is a heterogeneous disease, where chronic inflammation plays a key role in carcinogenesis. In this study, it is aimed to analyze the relationship with prognosis and chemotherapy response to clinicopathologicalnvariables in epithelial ovarian cancers such as proliferation of PD-1 +, CD8 +, CD4 +, CD3 + T-lymphocytes infiltrating the tumor and tumor stroma.
Material and methods: Seventy-six cases diagnosed with primary epithelial ovarian tumor from biopsy or surgical resection materials were included in the study. Immunreactivity of CD3, CD4, CD8, PD1 was evaluated immunohistochemically in lymphocytes in tumor infiltrating lymphocytes and stromal lymphocytes.
Results: Seventeen (22.4%) of the cases were Type I, 59 (77.6%) of them were Type II ovarian carcinoma. PD-1 positivity was observed in stromal and intraepithelial lymphocytes in 22 (28.9%) of 76 cases. In the presence of PD-1 + T-lymphocytes that infiltrate tumor and stroma, disease-free survival are shorter (p = 0.037). The presence of stromal CD4 + and CD8 + T-lymphocytes was more common in late stage patients (p = 0.012, p = 0.036; respectively). The disease-free and overall survival rate was statistically significantly shorter in the presence of CD8 + T lymphocytes (p = 0.009, p = 0.003; respectively).
Conclusions: CD3, CD4 and CD8 may contribute to PD-1 mediated tumor control. Anti PD-1 therapy may be an alternative to chemotherapy in PD-1 positive patients. Identifying patients who do not respond to chemotherapy through PD-1 expression prior to immunotherapy will help develop potential personalized immunotherapy.

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  1. Jammal MP, Lima CA, Murta EF, et al. Is ovarian cancer prevention currently still a recommendation of our grandparents? Rev Bras Ginecol Obstet. 2017; 39(12): 676–685.
  2. Wang L. Prognostic effect of programmed death-ligand 1 (PD-L1) in ovarian cancer: a systematic review, meta-analysis and bioinformatics study. J Ovarian Res. 2019; 12(1): 37.
  3. Lima CA, Jammal MP, Etchebehere RM, et al. Lymphocytes in peritumoral stroma: evaluation in epithelial ovarian neoplasms. Immunol Invest. 2020; 49(4): 397–405.
  4. Ladányi A, Somlai B, Gilde K, et al. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res. 2004; 10(2): 521–530.
  5. Sawada M, Goto K, Morimoto-Okazawa A, et al. PD-1+ Tim3+ tumor-infiltrating CD8 T cells sustain the potential for IFN-γ production, but lose cytotoxic activity in ovarian cancer. Int Immunol. 2020; 32(6): 397–405.
  6. Yamashita H, Nakayama K, Ishikawa M, et al. Relationship between microsatellite instability, immune cells infiltration, and expression of immune checkpoint molecules in ovarian carcinoma: immunotherapeutic strategies for the future. Int J Mol Sci. 2019; 20(20).
  7. Martin de la Fuente L, Westbom-Fremer S, Arildsen NS, et al. PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma. Virchows Arch. 2020; 477(1): 83–91.
  8. Tu L, Guan R, Yang H, et al. Assessment of the expression of the immune checkpoint molecules PD-1, CTLA4, TIM-3 and LAG-3 across different cancers in relation to treatment response, tumor-infiltrating immune cells and survival. Int J Cancer. 2020; 147(2): 423–439.
  9. Kim KiH, Choi KUn, Kim A, et al. PD-L1 expression on stromal tumor-infiltrating lymphocytes is a favorable prognostic factor in ovarian serous carcinoma. J Ovarian Res. 2019; 12(1): 56.
  10. Aksu ÖB, Şengül Ş. Immune Checkpoints and Inhibitors. Journal of Ankara University Faculty of Medicine. 2020; 72(3): 262–267.
  11. Kurman RJ, Shih IM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016; 186(4): 733–747.
  12. Zeppernick F, Meinhold-Heerlein I. The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer. Arch Gynecol Obstet. 2014; 290(5): 839–842.
  13. Okada Y, Yahata G, Takeuchi S, et al. A correlation between the expression of CD 8 antigen and specific cytotoxicity of tumor-infiltrating lymphocytes. Jpn J Cancer Res. 1989; 80(3): 249–256.
  14. Ernst B, Anderson KS. Immunotherapy for the treatment of breast cancer. Curr Oncol Rep. 2015; 17(2): 5.
  15. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008; 224(1): 166–182.
  16. Webb JR, Milne K, Nelson BH. PD-1 and CD103 are widely coexpressed on prognostically favorable intraepithelial CD8 T-Cells in human ovarian cancer. Cancer Immunol Res. 2015; 3(8): 926–935.
  17. Lamichhane P, Karyampudi L, Shreeder B, et al. IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. Cancer Res. 2017; 77(23): 6667–6678.
  18. Wieser V, Gaugg I, Fleischer M, et al. BRCA1/2 and TP53 mutation status associates with PD-1 and PD-L1 expression in ovarian cancer. Oncotarget. 2018; 9(25): 17501–17511.
  19. Mlynska A, Vaišnorė R, Rafanavičius V, et al. A gene signature for immune subtyping of desert, excluded, and inflamed ovarian tumors. Am J Reprod Immunol. 2020; 84(1): e13244.
  20. Clarke B, Tinker AV, Lee CH, et al. Intraepithelial T-cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 2009; 22(3): 393–402.
  21. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T-cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3): 203–213.
  22. Wang Q, Lou W, Di W, et al. Prognostic value of tumor PD-L1 expression combined with CD8 tumor infiltrating lymphocytes in high grade serous ovarian cancer. Int Immunopharmacol. 2017; 52: 7–14.
  23. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T-cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005; 102(51): 18538–18543.
  24. Doo DW, Norian LA, Arend RC. Checkpoint inhibitors in ovarian cancer: A review of preclinical data. Gynecol Oncol Rep. 2019; 29: 48–54.
  25. Yildirim N, Akman L, Acar K, et al. Do tumor-infiltrating lymphocytes really indicate favorable prognosis in epithelial ovarian cancer? Eur J Obstet Gynecol Reprod Biol. 2017; 215: 55–61.
  26. Singh M, Loftus T, Webb E, et al. Minireview: Regulatory T Cells and Ovarian Cancer. Immunol Invest. 2016; 45(8): 712–720.
  27. Hamanishi J, Mandai M, Abiko K, et al. The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors. Clin Immunol. 2011; 141(3): 338–347.
  28. Pinto MP, Balmaceda C, Bravo ML, et al. Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer. Gynecol Oncol. 2018; 151(1): 10–17.
  29. Le Page C, Marineau A, Bonza PK, et al. BTN3A2 expression in epithelial ovarian cancer is associated with higher tumor infiltrating T-cells and a better prognosis. PLoS One. 2012; 7(6): e38541.
  30. Yang L, Wang S, Zhang Qi, et al. Clinical significance of the immune microenvironment in ovarian cancer patients. Mol Omics. 2018; 14(5): 341–351.
  31. Iwai Y, Hamanishi J, Chamoto K, et al. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 2017; 24(1): 26.
  32. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016; 54: 139–148.
  33. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015; 33(34): 4015–4022.
  34. Hamanishi J, Mandai M, Ikeda T, et al. Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. Journal of Clinical Oncology. 2015; 33(15_suppl): 5570–5570.
  35. Normann MC, Türzer M, Diep LMy, et al. Early experiences with PD-1 inhibitor treatment of platinum resistant epithelial ovarian cancer. J Gynecol Oncol. 2019; 30(4): e56.