The investigation of PD-L1 expression as a prognostic marker for uterine sarcoma.

Authors

DOI:

https://doi.org/10.26641/1997-9665.2018.2.62-71

Keywords:

uterine sarcoma, tumor-marker expression, PD-L1, prognostic factor

Abstract

Background. The uterine sarcoma is a rare tumor with the unpredictable, aggressive clinical behavior. Medical science relies on the development of reliable tumor markers, on the basis of which the optimal treatment program can be chosen, and will be also possible to make a prognosis. The hyperexpression of PD-L1 in many cases correlates with unfavorable prognosis of the disease and is an important prognostic biomarker for some types of tumors: melanoma, kidney cancer, non-small cell lung cancer. The role of PD-L1 expression, as a tumor marker in sarcoma, remains unclear. Objective. The investigation of PD-L1 expression as a prognostic tumor marker for uterine sarcoma. Methods. There have been selected 30 uterine sarcoma patients stage I-II (T1-2NxM0), for immunohistochemistry analyze of PD-L1 expression. Depending on the morphological tumor types all the patients were distributed: leiomyosarcoma (LMS) - 20.0%, endometrial stromal sarcoma (ESS) - 46.7%, undifferentiated sarcoma (HC) - 33.3%. Results. Our results showed that 73.3 % of patients with uterine sarcoma exhibited low expression level of PD-L1. The moderate level and overexpression of PD-L1 were observed in undifferentiated and endometrial stromal sarcoma - 13.3 and 6.7 %, respectively. At further follow-up of patients with PD-L1 expression, the relapse of the disease was detected in 50.0 % of cases. Conclusion. The PD-L1 expression in tumor tissue, regardless of its level, is considered to be an unfavorable prognostic factor for uterine sarcoma patients. In case of moderate expression level of PD-L1, so as at its overexpression, the tumor progression was detected in 83.3% of uterine sarcoma patients.

References

  1. Liao Y, Feng Y, Shen J, Hornicek FJ, Duan Zh. The roles and therapeutic potential of cyclin-dependent kinases (CDKs) in sarcoma. Cancer and Metastasis Reviews. 2016;35(2):151-63. https://doi.org/10.1007/s10555-015-9601-1.
  2. Nakamura T, Hamuro J, Takaishi M, Sim-mons S, Maruyama K, Zaffalon A, Bentley AJ, Ka-wasaki S, Nagata-Takaoka M, Fullwood NJ, Itami S, Sano S, Ishii M, Barrandon Y, Kinoshita S. LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis. J. Clin. Invest. 2014;124:385-97. http://doi.org/10.1172/JCI71488.
  3. D'Angelo E, Prat J. Uterine sarcomas: a re-view. Gynecol Oncol. 2010;116:131-9. https://doi.org/10.1016/j.ygyno.2009.09.023.
  4. Sukhin VS, Dolhaia OV. [Features of mor-phology of uterine sarcoma]. Problems of continu-ous medical training and science. 2017;4(27):79-87. Ukrainian.
  5. Brinkkoetter PT, Pippin JW, Shankland SJ. Cyclin I-Cdk5 governs survival in post-mitotic cells. Cell Cycle. 2010;9:1729-31. https://doi.org/10.4161/cc.9.9.11471.
  6. Rondahl V, Holmlund C, Karlsson T, Wang B, Faraz M, Henriksson R, Hedman H. Lrig2-deficient mice are protected against PDGFB-induced glioma. PLoS One. 2013;8(9):e73635. http://doi.org/10.1371/journal.pone.0073635.
  7. Kadagidze ZG, Chertkova AI. [New ap-proaches to increasing the effectiveness of the anti-tumor immune response]. Immunology. 2015;1:66-70. Russian.
  8. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 2007;19(7):813-24. https://doi.org/10.1093/intimm/dxm057.
  9. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 2000;192(7):1027-34. PMID: 11015443.
  10. Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22(5):265-8. PMID: 11323285.
  11. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM. PD-1: PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 2002;32(3):634-43. https://doi.org/10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9.
  12. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2001;2(3):261-8. https://doi.org/10.1038/85330.
  13. Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N. Engl. J. Med. 2016;375:1767-78. https://doi.org/10.1056/NEJMra1514296.
  14. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-7. https://doi.org/10.1038/nature14011.
  15. Skubitz KM, Skubitz AP. Differential gene expression in leiomyosarcoma. Cancer. 2003;98:1029-38. http://doi.org/10.1002/cncr.11586.
  16. Kim JR, Moon YJ, Kwon KS, Bae JS, Wagle S, Kim KM, Park HS, Lee H, Moon WS, Chung MJ, Kang MJ, Jang KY. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS ONE. 2013;8(12):e82870. https://doi.org/ 10.1371/journal.pone.0082870.
  17. D’Angelo SP, Tap WD, Schwartz GK, Carvajal RD. Sarcoma immunotherapy: past ap-proaches and future directions. Review Article. Sar-coma. 2014;39:1967. http://doi.org/10.1155/2014/391967.
  18. Mitsis D, Francescutti V, Skitzki J. Current Immunotherapies for Sarcoma: Clinical Trials and Rationale. Review Article. Sarcoma. 2016;97:57219. http://doi.org/10.1155/2016/9757219.
  19. Figo committee on gynecologic oncology. FIGO staging for uterine sarcomas. Int. J. Gynaecol. Obstet. 2009;104(3):177-8. https://doi.org/10.1016/j.ijgo.2008.12.008.
  20. Sukhin VS. Surgical treatment of uterine sarcoma patients. Review. Women’s Health. 2014;91(5):46-9.
  21. Cadoo KA, Gucalp A, Traina TA. Palbociclib: an evidence-based review of its poten-tial in the treatment of breast cancer. Breast Cancer. 2014;6:123-33. https://doi.org/10.2147/BCTT.S46725.
  22. Kim C, Kim EK, Jung H, Chon HJ, Han JW, Shin KH, Hu H, Kim KS, Choi YD, Kim S, Lee YH, Suh JS, Ahn JB, Chung HC, Noh SH, Rha SY, Kim SH, Kim HS. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer. 2016;16:434. https://doi.org/10.1186/s12885-016-2451-6.
  23. Matsumura N, Mandai M, Miyanishi M, Fukuhara K, Baba T, Higuchi T, Kariya M, Takakura K, Fujii S. Oncogenic property of acrogranin in human uterine leiomyosarcoma: direct evidence of genetic contribution in in vivo tumorigenesis. Clin. Cancer Res. 2006;12(5):1402-11. http://doi.org/10.1158/1078-0432.CCR-05-2003.
  24. Benassi MS, Gamberi G, Magagnoli G, Molendini L, Ragazzini P, Merli M, Chiesa F, Balladelli A, Manfrini M, Bertoni F, Mercuri M, Picci P. Metalloproteinase expression and prognosis in soft tissue sarcomas. Ann. Oncol., 2001;12:75-8. https://doi.org/10.1023/A:1008318614461.
  25. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation- induced cancer: crosstalk between tumours, immune cells and mi-croorganisms. Nat Rev Cancer. 2013;13(11):759–71. https://doi.org/10.1038/nrc3611.
  26. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer. 2009;9:153-66. http://doi.org/10.1038/nrc2602.
  27. Kljuchagina JI, Sokolova ZA, Baryshnikova MA. [Role of PD-1 receptor and its ligands PD-L1 and PD-L2 in cancer immunothera-py]. Oncopediatry. 2017;4(1):49-55. https://doi.org/10.15690/onco.v4i1.1684.
  28. Toulmonde M, Adam J, Bessede A, Ranchère-Vince D, Velasco V, Brouste V, Blay J-Y, Mir O, Italiano A. Integrative assessment of expres-sion and prognostic value of PDL1, IDO, and kynurenine in 371 primary soft tissue sarcomas with genomic complexity. J. Clin. Oncol. 2016;34(15):11008. http://doi.org/10.1200/JCO.2016.34.15_suppl.11008.
  29. Callahan MK, Wolchok JD. At the Bedside: cTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J. Leukoc. Biol. 2013;94:41-53. https://doi.org/10.1189/jlb.1212631.
  30. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 2007;56(8):1173-82. http://doi.org/10.1007/s00262-006-0266-z.
  31. Liokumovich P, Goldberg I, Davidson B, Gotlieb WH, Zahavi T, Ben-Baruch G, Reder I, Kopolovic J. Expression of metalloproteinases en-dometrial stromal sarcoma: immunohistochemical study using image analysis. J. Clin. Pathol. 1999;52:198-202. PMID: 10450179.
  32. Sabah M, Cummins R, Leader M, Kay E. Aberrant expression of the Rb pathway proteins in soft tissue sarcomas. Appl Immunohistochem. Mol. Morphol. 2006;14(4):397-403. http://doi.org/10.1097/01.pai.0000190176.06200.68.
  33. Rumjancev AA, Tjuljandin SA. [Efficacy of inhibitors of immune response control points in the treatment of solid tumors]. Practical oncology. 2016;17(2):74-89. Russian.
  34. Swaika A, Hammond WA, Joseph RW. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol. Immunol. 2015;67(2 Pt. A):4–17. http://doi.org/10.1016/j.molimm.2015.02.009.
  35. Bhattacharyya T, Purushothaman K, Puthiyottil SS, Bhattacharjee A, Muttah G. Immunological interactions in radiotherapy – opening a new window of opportunity. Ann. Transl. Med. 2016;4(3):51. PMID:26904573.
  36. Contreras-Vallejos E, Utreras E, Gonzalez-Billault C. Going out of the brain: non-nervous system physiological and pathological functions of Cdk5. Cellular Signalling. 2012;24:44-52. https://doi.org/10.1016/j.cellsig.2011.08.022.
  37. Davidson B, Abeler VM, Førsund M, Holth A, Yang Y, Kobayashi Y, Chen L, Kristensen GB, Shih I-M, Wang T-L. Gene expression signatures of primary and metastatic uterine leiomyosarcoma. Hum Pathol. 2014;45(4):691-700. https://doi.org/10.1016/j.humpath.2013.11.003.
  38. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH. Tissue expression of PD-L1 mediates peripheral T-cell tolerance. J. Exp. Med. 2006;203(4):883-95. https://doi.org/10.1084/jem.20051776.
  39. Tang X, Wang X, Gong X, Tong M, Park D, Xia Z, Mao Z. Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 2005;25(19):4823-34. http://doi.org/10.1523/JNEUROSCI.1331-05.2005.
  40. Benassi MS, Magagnoli G, Ponticelli F, Pazzaglia L, Zanella L, Gamberi G, Ragazzini P, Ferrari C, Mercuri M, Picci P. Tissue and serum loss of metalloproteinase inhibitors in high grade soft tissue sarcomas. Histol. Histopathol. 2003;18(4):1035-40. https://doi.org/10.14670/HH-18.1035.
  41. Moffatt P, Thomas GP. Osteocrin – beyond just another bone protein? Cell Mol. Life Sci. 2009;66:1135-9.
  42. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br. J. Cancer. 2013;108(8):1560-5. http://doi.org/10.1038/bjc.2013.117.
  43. Chu F, Neelapu SS. Anti-PD-1 antibodies for the treatment of B-cell lymphoma: Importance of PD-1+ T-cell subsets. Oncoimmunology. 2014;3(1):e28101. https://doi.org/10.4161/onci.28101.
  44. Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell Biol. 2013;33:3091-8. http://doi.org/10.1128/MCB.00319-13.
  45. Zhang J, Krishnamurthy PK, Johnson GV. Cdk5 phosphorylates p53 and regulates its activity. J. Neurochem. 2002;81(2):307-13. PMID: 12064478.
  46. VanArsdale T, Boshoff C, Arndt KT, Ab-raham RT. Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment. Clin. Cancer Res. 2015;21(13):2905-10. http://doi.org/10.1158/1078-0432.CCR-14-0816.
  47. Zhai YL, Nikaido T, Toki T, Shiozawa A, Orii A, Fujii S. Prognostic significance of bcl-2 ex-pression in leiomyosarcoma of the uterus. Br. J. Cancer. 1999;80:1658-64. http://doi.org/10.1038/sj.bjc.6690578.

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Sukhin, V. S., Danyliuk, S. V., Sukhina, O. N., Zadnepryanniy, A. V., Lindquist, D., Hermelin, H., & Tarján, M. (2018). The investigation of PD-L1 expression as a prognostic marker for uterine sarcoma. Морфологія / Morphologia / Morfologìâ, 12(2), 62–71. https://doi.org/10.26641/1997-9665.2018.2.62-71

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Vol. 12 No. 2 (2018)

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