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Tumor-Associated T-Lymphocytes and Macrophages are Decreased in Endometrioid Endometrial Carcinoma with MELF-Pattern Stromal Changes

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Cancer Microenvironment

Abstract

Microcystic, elongated, fragmented (MELF)-pattern is an unusual morphology of myometrial invasive front in endometrioid endometrial carcinoma (EA). The aim of the study was to investigate potential correlation between MELF-pattern and peritumoral inflammatory immune response. A total of 96 out of 368 patients were included in this study. CD3, CD20, CD57. CD68 and S100 markers were used for the detection of tumor-associated T-lymphocytes (TAT), tumor-associated B-lymphocytes (TAB), tumor-associated NK-lymphocytes (NK), tumor-associated macrophages and dendritic cells respectively. Mann-Whitney tests, receiver operating characteristic (ROC) curve analysis, and Spearman correlation were used as methods for statistical analyses. Odds ratio with 95% confidence interval (95% CI) was determined with the use of a logistic regression model. A p < 0.05 was considered statistically significant. Our results suggested that the number of CD3 and CD68 cells were significantly lower (p < 0.001) in cases of endometrioid carcinoma with MELF-pattern. A significant correlation between the presence of MELF-pattern and decrease of CD3 positive T-lymphocytes (r = 0.691; p < 0.001) was also observed. Additionally, we found an inverse correlation between the presence of MELF-pattern and TAM (r = 0.568; p = 0.001). Therefore, our data suggest that MELF-pattern may be associated with EA stroma fibrosis that contains immune cells infiltration and demonstrated a decrease in the number of TAT and TAM cells. This may indicate the poor clinical prognosis of this disease.

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References

  1. Kojiro-Sanada S, Yasuda K, Nishio S et al (2017) CXCL14-CXCR4 and CXCL12-CXCR4 axes may play important roles in the unique invasion process of endometrioid carcinoma with MELF-pattern myoinvasion. Int J Gynecol Pathol 36:530–539. https://doi.org/10.1097/pgp.0000000000000362

    Article  CAS  PubMed  Google Scholar 

  2. Naki MM, Oran G, Tetikkurt SÜ et al (2017) Microcystic, elongated and fragmented (MELF) pattern of invasion in relation to histopathological and clinical prognostic factors in endometrioid endometrial adenocarcinoma. Journal of the Turkish-German Gynecological Association. https://doi.org/10.4274/jtgga.2017.0016

  3. Kihara A, Yoshida H, Watanabe R et al (2017) Clinicopathologic association and prognostic value of microcystic, elongated, and fragmented (MELF) pattern in endometrial endometrioid carcinoma. Am J Surg Pathol 41:896–905. https://doi.org/10.1097/pas.0000000000000856

    Article  PubMed  Google Scholar 

  4. Sanci M, Güngördük K, Gülseren V et al (2017) MELF pattern for predicting lymph node involvement and survival in grade I-II endometrioid-type endometrium cancer. Int J Gynecol Pathol:1. https://doi.org/10.1097/pgp.0000000000000370

  5. Stewart CJR, Little L (2009) Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial-mesenchymal transition. Histopathology 55:91–101. https://doi.org/10.1111/j.1365-2559.2009.03327.x

    Article  PubMed  Google Scholar 

  6. Stewart CJ, Crook ML (2010) Galectin-3 expression in uterine endometrioid adenocarcinoma. Int J Gynecol Pathol 29:555–561. https://doi.org/10.1097/pgp.0b013e3181e4ee4ea

    Article  PubMed  Google Scholar 

  7. Petty AJ, Yang Y (2017) Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy 9:289–302. https://doi.org/10.2217/imt-2016-0135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437. https://doi.org/10.1038/nm.3394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shurin MR et al. (2016) Tumor Immunoenvironment. Springer, S.l.

  10. Zinovkin DA, Pranjol MZI, Petrenyov DR et al (2017) The potential roles of MELF-pattern, microvessel density, and vegf expression in survival of patients with endometrioid endometrial carcinoma: a morphometrical and immunohistochemical analysis of 100 cases. Journal of Pathology and Translational Medicine 51:456–462. https://doi.org/10.4132/jptm.2017.07.19

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zinovkin D, Pranjol MZI (2016) Tumor-infiltrated lymphocytes, macrophages, and dendritic cells in endometrioid adenocarcinoma of corpus uteri as potential prognostic factors. Int J Gynecol Cancer 26:1207–1212. https://doi.org/10.1097/igc.0000000000000758

    Article  PubMed  Google Scholar 

  12. Dunn GP, Bruce AT, Ikeda H et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998. https://doi.org/10.1038/ni1102-991

    Article  CAS  PubMed  Google Scholar 

  13. Seager RJ, Hajal C, Spill F et al (2017) Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression. Convergent Science Physical Oncology 3:034002. https://doi.org/10.1088/2057-1739/aa7e86

    Article  PubMed  PubMed Central  Google Scholar 

  14. Maluf PJ, Michelin MA, Etchebehere RM et al (2008) T lymphocytes (CD3) may participate in the recurrence of cervical intraepithelial neoplasia grade III. Arch Gynecol Obstet 278:525–530. https://doi.org/10.1007/s00404-008-0621-8

    Article  CAS  PubMed  Google Scholar 

  15. Brand A, Singer K, Koehl GE et al (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by t and nk cells. Cell Metab 24:657–671. https://doi.org/10.1016/j.cmet.2016.08.011

    Article  CAS  PubMed  Google Scholar 

  16. Dietl K, Renner K, Dettmer K et al (2009) Lactic acid and acidification inhibit tnf secretion and glycolysis of human monocytes. J Immunol 184:1200–1209. https://doi.org/10.4049/jimmunol.0902584

    Article  CAS  PubMed  Google Scholar 

  17. Spaner D, Bahlo A (2011) B lymphocytes in cancer immunology. In: Medin J, Fowler D (eds) Experimental and applied immunotherapy. Humana Press, Totowa, NJ

    Google Scholar 

  18. Stakheeva M, Riabov V, Mitrofanova I et al (2017) Role of the immune component of tumor microenvironment in the efficiency of cancer treatment: perspectives for the personalized therapy. Curr Pharm Des 23:1–20. https://doi.org/10.2174/1381612823666170714161703

    Article  CAS  Google Scholar 

  19. Pegram HJ, Haynes NM, Smyth MJ et al (2010) Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. Cancer Immunol Immunother 59:1235–1246. https://doi.org/10.1007/s00262-010-0848-7

    Article  PubMed  Google Scholar 

  20. Levy E, Bianchini M, Euw EV et al (2008) Human leukocyte antigen-E protein is overexpressed in primary human colorectal cancer. Int J Oncol. https://doi.org/10.3892/ijo.32.3.633

  21. Yuan A, Chen JJW, Yang PC (2008) Pathophysiology of tumor-associated macrophages. Adv Clin Chem:199–223. https://doi.org/10.1016/s0065-2423(07)00008-x

    Google Scholar 

  22. Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180:2011–2017. https://doi.org/10.4049/jimmunol.180.4.2011

    Article  CAS  PubMed  Google Scholar 

  23. Slayton WB, Hu Z (2010) Bone marrow stroma and the leukemic microenvironment. In: Tumor microenvironment, pp 99–133. https://doi.org/10.1002/9780470669891.ch6

    Chapter  Google Scholar 

  24. Ha SY, Yeo S-Y, Xuan Y-H, Kim S-H (2014) The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma. PLoS One 9:e99955. https://doi.org/10.1371/journal.pone.0099955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zheng X, Turkowski K, Mora J et al (2017) Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget 8:48436–48452. https://doi.org/10.18632/oncotarget.17061

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shurin MR, Salter RD (2009) Dendritic cells in cancer. Springer, New York, NY

    Google Scholar 

  27. Tashireva LA, Perelmuter VM, Manskikh VN, et al (2017) Types of immune-inflammatory responses as a reflection of cell–cell interactions under conditions of tissue regeneration and tumor growth. Biochem Mosc 82:542–555. https://doi.org/10.1134/s0006297917050029

    Article  CAS  Google Scholar 

  28. Pasqual G, Chudnovskiy A, Tas JMJ et al (2018) Monitoring T cell–dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature 553:496–500. https://doi.org/10.1038/nature25442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Janco JMT, Lamichhane P, Karyampudi L, Knutson KL (2015) Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol 194:2985–2991. https://doi.org/10.4049/jimmunol.1403134

    Article  CAS  Google Scholar 

  30. Becht E, Giraldo NA, Germain C et al (2016) Immune contexture, Immunoscore, and malignant cell molecular subgroups for prognostic and Theranostic classifications of cancers. Advances in Immunology Tumor Immunology:95–190. https://doi.org/10.1016/bs.ai.2015.12.002

    Google Scholar 

  31. Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306. https://doi.org/10.1038/nrc3245

    Article  CAS  PubMed  Google Scholar 

  32. Becht E, Giraldo NA, Dieu-Nosjean M-C et al (2016) Cancer immune contexture and immunotherapy. Curr Opin Immunol 39:7–13. https://doi.org/10.1016/j.coi.2015.11.009

    Article  CAS  PubMed  Google Scholar 

  33. Jiang H, Hegde S, Denardo DG (2017) Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy. Cancer Immunol Immunother 66:1037–1048. https://doi.org/10.1007/s00262-017-2003-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the patients who agreed for participating in this study and reviewers for their constructive comments.

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Authors and Affiliations

  1. Department of Pathology, Gomel State Medical University, Lange str. 5, Gomel, 246029, Republic of Belarus

    Dmitry Aleksandrovich Zinovkin, Il’ya Andreevich Bilsky & Valeriya Alexandrovna Zmushko

  2. William Harvey Research Institute, Barts & The London School of Medicine & Dentistry Queen Mary University of London, London, UK

    Md Zahidul Islam Pranjol

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  1. Dmitry Aleksandrovich Zinovkin
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  2. Md Zahidul Islam Pranjol
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  3. Il’ya Andreevich Bilsky
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  4. Valeriya Alexandrovna Zmushko
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Correspondence to Dmitry Aleksandrovich Zinovkin.

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All authors declare that they have no conflict of interest.

Ethical Approval

The study was approved by the Committees for Medical and Health Sciences of Research Ethics of Gomel State Medical University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Dispensation from the requirement of patient consent was granted.

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Zinovkin, D.A., Pranjol, M.Z.I., Bilsky, I.A. et al. Tumor-Associated T-Lymphocytes and Macrophages are Decreased in Endometrioid Endometrial Carcinoma with MELF-Pattern Stromal Changes. Cancer Microenvironment 11, 107–114 (2018). https://doi.org/10.1007/s12307-018-0213-5

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  • DOI: https://doi.org/10.1007/s12307-018-0213-5

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