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Blockade pf CD73/adenosine axis improves the therapeutic efficacy of docetaxel in epithelial ovarian cancer

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Abstract

Background

Epithelial ovarian cancer (EOC) is the most common and lethal ovarian cancer which threatens women health. Nowadays, the standard treatment is maximal cytoreductive surgical debulking followed by chemotherapy. However, immunosuppressive environment generated by chemotherapy, which can be reversed by immunotherapy, leads to the failure of standard treatment. Therefore, a combination of chemotherapy and immunotherapy will be a promising strategy for EOC patients.

Method

For in vitro study, CD73 expression, CD73 activity, and CD8+ T-cell proliferation were measured after docetaxel (DTXL) treatment with or without CD73 antibody. For in vivo study, tumor growth, tumor weight, and the population of various immune cells in the tumor were analyzed in different drug treatment groups.

Results

DTXL can increase both the CD73 expression and enzymatic activity in patient-derived epithelial cell and ID8 cell while causing immunosuppressive response which was reversed by anti-CD73 antibody (aCD73). Moreover, tumor growth and lung metastasis in mouse were significantly diminished after DTXL + aCD73 treatment.

Conclusion

Blocking CD73/adenosine pathway could reverse the immunosuppression caused by DTXL, and a combination of DTXL with CD73 inhibitor or anti-CD73 antibody would be a more effective and promising therapy for EOC.

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References

  1. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387

    Article  PubMed  Google Scholar 

  2. Reid BM, Permuth JB, Sellers TA (2017) Epidemiology of ovarian cancer: a review. Cancer Biol Med 14(1):9–32. https://doi.org/10.20892/j.issn.2095-3941.2016.0084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Desai A, Xu J, Aysola K, Qin Y, Okoli C, Hariprasad R, Chinemerem U, Gates C, Reddy A, Danner O, Franklin G, Ngozi A, Cantuaria G, Singh K, Grizzle W, Landen C, Partridge EE, Rice VM, Reddy ES, Rao VN (2014) Epithelial ovarian cancer: an overview. World J Transl Med 3(1):1–8. https://doi.org/10.5528/wjtm.v3.i1.1

    Article  PubMed  PubMed Central  Google Scholar 

  4. Guppy AE, Nathan PD, Rustin GJ (2005) Epithelial ovarian cancer: a review of current management. Clin Oncol (Royal College of Radiologists (Great Britain)) 17(6):399–411

    Article  CAS  Google Scholar 

  5. Coward JI, Middleton K, Murphy F (2015) New perspectives on targeted therapy in ovarian cancer. Int J Womens Health 7:189–203. https://doi.org/10.2147/ijwh.s52379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim A, Ueda Y, Naka T, Enomoto T (2012) Therapeutic strategies in epithelial ovarian cancer. J Exp Clin Cancer Res CR 31:14. https://doi.org/10.1186/1756-9966-31-14

    Article  CAS  PubMed  Google Scholar 

  7. Mittica G, Genta S, Aglietta M, Valabrega G (2016) Immune checkpoint inhibitors: a new opportunity in the treatment of ovarian cancer? Int J Mol Sci. https://doi.org/10.3390/ijms17071169

    Article  PubMed  PubMed Central  Google Scholar 

  8. Piccart MJ, Gore M, Ten Bokkel Huinink W, Van Oosterom A, Verweij J, Wanders J, Franklin H, Bayssas M, Kaye S (1995) Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 87(9):676–681

    Article  CAS  PubMed  Google Scholar 

  9. Cristea M, Han E, Salmon L, Morgan RJ (2010) Practical considerations in ovarian cancer chemotherapy. Ther Adv Med Oncol 2(3):175–187. https://doi.org/10.1177/1758834010361333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Katsumata N (2003) Docetaxel: an alternative taxane in ovarian cancer. Br J Cancer 89(Suppl 3):S9–s15. https://doi.org/10.1038/sj.bjc.6601495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yvon AM, Wadsworth P, Jordan MA (1999) Taxol suppresses dynamics of individual microtubules in living human tumor cells. Mol Biol Cell 10(4):947–959. https://doi.org/10.1091/mbc.10.4.947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lyseng-Williamson KA, Fenton C (2005) Docetaxel: a review of its use in metastatic breast cancer. Drugs 65(17):2513–2531. https://doi.org/10.2165/00003495-200565170-00007

    Article  CAS  PubMed  Google Scholar 

  13. Wellenstein MD, de Visser KE (2018) Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity 48(3):399–416. https://doi.org/10.1016/j.immuni.2018.03.004

    Article  CAS  PubMed  Google Scholar 

  14. Anderson KG, Stromnes IM, Greenberg PD (2017) Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31(3):311–325. https://doi.org/10.1016/j.ccell.2017.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S (2014) PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS ONE 9(2):e89350. https://doi.org/10.1371/journal.pone.0089350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mantia-Smaldone GM, Corr B, Chu CS (2012) Immunotherapy in ovarian cancer. Hum Vaccines Immunother 8(9):1179–1191. https://doi.org/10.4161/hv.20738

    Article  CAS  Google Scholar 

  17. Rodriguez GM, Galpin KJC, McCloskey CW, Vanderhyden BC (2018) The tumor microenvironment of epithelial ovarian cancer and its influence on response to immunotherapy. Cancers. https://doi.org/10.3390/cancers10080242

    Article  PubMed  PubMed Central  Google Scholar 

  18. Antonioli L, Blandizzi C, Malavasi F, Ferrari D, Hasko G (2016) Anti-CD73 immunotherapy: a viable way to reprogram the tumor microenvironment. Oncoimmunology 5(9):e1216292. https://doi.org/10.1080/2162402x.2016.1216292

    Article  PubMed  PubMed Central  Google Scholar 

  19. Leone RD, Emens LA (2018) Targeting adenosine for cancer immunotherapy. J Immunother Cancer 6(1):57. https://doi.org/10.1186/s40425-018-0360-8

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zhang B (2010) CD73: a novel target for cancer immunotherapy. Can Res 70(16):6407–6411. https://doi.org/10.1158/0008-5472.can-10-1544

    Article  CAS  Google Scholar 

  21. Young A, Ngiow SF, Barkauskas DS, Sult E, Hay C, Blake SJ, Huang Q, Liu J, Takeda K, Teng MWL, Sachsenmeier K, Smyth MJ (2016) Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 30(3):391–403. https://doi.org/10.1016/j.ccell.2016.06.025

    Article  CAS  PubMed  Google Scholar 

  22. Jin D, Fan J, Wang L, Thompson LF, Liu A, Daniel BJ, Shin T, Curiel TJ, Zhang B (2010) CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Can Res 70(6):2245–2255. https://doi.org/10.1158/0008-5472.can-09-3109

    Article  CAS  Google Scholar 

  23. Theriault BL, Portelance L, Mes-Masson AM, Nachtigal MW (2013) Establishment of primary cultures from ovarian tumor tissue and ascites fluid. Methods Mol Biol (Clifton, NJ) 1049:323–336. https://doi.org/10.1007/978-1-62703-547-7_24

    Article  CAS  Google Scholar 

  24. Yao YD, Sun TM, Huang SY, Dou S, Lin L, Chen JN, Ruan JB, Mao CQ, Yu FY, Zeng MS, Zang JY, Liu Q, Su FX, Zhang P, Lieberman J, Wang J, Song E (2012) Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. Sci Transl Med 4(130):130ra148. https://doi.org/10.1126/scitranslmed.3003601

    Article  Google Scholar 

  25. Su F, Kozak KR, Imaizumi S, Gao F, Amneus MW, Grijalva V, Ng C, Wagner A, Hough G, Farias-Eisner G, Anantharamaiah GM, Van Lenten BJ, Navab M, Fogelman AM, Reddy ST, Farias-Eisner R (2010) Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer. Proc Natl Acad Sci USA 107(46):19997–20002. https://doi.org/10.1073/pnas.1009010107

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Heze Municipal Hospital of Shandong Province, No. 2888 Caozhou Road, Heze, 274000, Shandong, China

    Hongmei Li

  2. Department of Health, Heze Municipal Hospital of Shandong Province, No. 2888 Caozhou Road, Heze, 274000, Shandong, China

    Meihua Lv

  3. Department of Gynaecology, Heze Municipal Hospital of Shandong Province, No. 2888 Caozhou Road, Heze, 274000, Shandong, China

    Baohua Qiao & Xia Li

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  1. Hongmei Li
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  2. Meihua Lv
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  3. Baohua Qiao
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  4. Xia Li
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Contributions

Data collection and analysis: HL, ML, BQ, and XL; study designed and manuscript writing: XL. All authors approved the final submission.

Corresponding author

Correspondence to Xia Li.

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The authors declare that they have no conflicts of interest to disclose.

Research involving human participants and/or animals

Human study was approved by the Ethical Committee in Heze Municipal Hospital of Shandong Province. All animal studies were in accordance with Guide for the Care and Use of Laboratory Animals (8th edition, NIH), and approved by the Institutional Animal Care and Use Committee in Heze Municipal Hospital of Shandong Province.

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Li, H., Lv, M., Qiao, B. et al. Blockade pf CD73/adenosine axis improves the therapeutic efficacy of docetaxel in epithelial ovarian cancer. Arch Gynecol Obstet 299, 1737–1746 (2019). https://doi.org/10.1007/s00404-019-05139-3

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  • DOI: https://doi.org/10.1007/s00404-019-05139-3

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