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Infiltration of T cells promotes the metastasis of ovarian cancer cells via the modulation of metastasis-related genes and PD-L1 expression

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Abstract

Due to its high ability to disseminate, ovarian cancer remains one of the largest threats to women’s health, worldwide. Evidence showed that the immune cells infiltrating the tumor microenvironment are crucial in mediating metastasis. Therefore, it is necessary to understand which types of immune cells are involved in metastasis, and to determine the mechanisms by which they influence the process. By immunohistochemistry, we found that higher concentrations of intratumoral CD8+ T cells were found to be correlated with an advanced grade and stage of ovarian cancer. Additionally, the infiltration of stromal CD8+ T cells was also significantly higher in tissues with advanced stages and metastatic tumors. A positive correlation between the infiltration of FoxP3+ Treg cells and histological grade was also observed, regardless of location. PD-L1 expression in metastatic tumors was also higher than that in paired primary ovarian tumors. Transwell migration and invasion assays revealed the increased migration and invasion of ovarian cancer cell lines (A2780CP and ES2) and ascites-derived ovarian cancer cells following co-culturing with CD8+ T cells. Enhanced expression of MMP-9, uPA, VEGF, bFGF, IL-8, IL-10, and PD-L1 by cancer cells following co-culturing with CD8+ T cells were also detected by qPCR, ELISA or flow cytometry. In conclusion, our findings suggest that the infiltrated T cells could promote the development of ovarian cancer, and provide another mechanism of immune evasion mediated by T cells.

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References

  1. American Cancer Society (2011) Cancer Facts & Figures 2011. Atlanta: American Cancer Society

  2. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics. CA Cancer J Clin 68(4):284–296. https://doi.org/10.3322/caac.21456

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  4. Kulbe H, Chakravarty P, Leinster DA, Charles KA, Kwong J, Thompson RG, Coward JI, Schioppa T, Robinson SC, Gallagher WM, Galletta L, Australian Ovarian Cancer Study G, Salako MA, Smyth JF, Hagemann T, Brennan DJ, Bowtell DD, Balkwill FR (2012) A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Can Res 72(1):66–75. https://doi.org/10.1158/0008-5472.CAN-11-2178

    Article  Google Scholar 

  5. Reinartz S, Schumann T, Finkernagel F, Wortmann A, Jansen JM, Meissner W, Krause M, Schworer AM, Wagner U, Muller-Brusselbach S, Muller R (2014) Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer J Int Du Cancer 134(1):32–42. https://doi.org/10.1002/ijc.28335

    Article  CAS  Google Scholar 

  6. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266. https://doi.org/10.1016/j.cell.2006.01.007

    Article  CAS  PubMed  Google Scholar 

  7. Drakes ML, Stiff PJ (2018) Regulation of ovarian cancer prognosis by immune cells in the tumor microenvironment. Cancers (Basel). https://doi.org/10.3390/cancers10090302

    Article  Google Scholar 

  8. Casares N, Arribillaga L, Sarobe P, Dotor J, Lopez-Diaz de Cerio A, Melero I, Prieto J, Borras-Cuesta F, Lasarte JJ (2003) CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 171(11):5931–5939

    Article  CAS  PubMed  Google Scholar 

  9. Maloy KJ, Powrie F (2001) Regulatory T cells in the control of immune pathology. Nat Immunol 2(9):816–822. https://doi.org/10.1038/ni0901-816

    Article  PubMed  CAS  Google Scholar 

  10. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) 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 102(51):18538–18543. https://doi.org/10.1073/pnas.0509182102

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E, Deibl M, Gastl G, Gunsilius E, Marth C (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11(23):8326–8331. https://doi.org/10.1158/1078-0432.CCR-05-1244

    Article  PubMed  CAS  Google Scholar 

  12. Shepherd TG, Theriault BL, Campbell EJ (2007) Nachtigal MW (2015) Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients (vol 1, pg 2643, 2007). Nat Protoc 10(9):1457–1457. https://doi.org/10.1038/nprot0915-1457b

    Article  CAS  Google Scholar 

  13. Wang J-J, Siu MK, Jiang Y-X, Leung TH, Chan DW, Cheng R-R, Cheung AN, Ngan HY, Chan KK (2019) Aberrant upregulation of PDK1 in ovarian cancer cells impairs CD8+ T cell function and survival through elevation of PD-L1. OncoImmunology 8(11):1659092. https://doi.org/10.1080/2162402X.2019.1659092

    Article  Google Scholar 

  14. Shi J, Wei PK (2015) Low-dose interleukin-8 induces the adhesion, migration and invasion of the gastric cancer SGC-7901 cell line. Oncol Lett 10(5):2871–2877. https://doi.org/10.3892/ol.2015.3641

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Mustea A, Konsgen D, Braicu EI, Pirvulescu C, Sun P, Sofroni D, Lichtenegger W, Sehouli J (2006) Expression of IL-10 in patients with ovarian carcinoma. Anticancer Res 26(2C):1715–1718

    PubMed  CAS  Google Scholar 

  16. Lane D, Matte I, Garde-Granger P, Bessette P, Piche A (2018) Ascites IL-10 promotes ovarian cancer cell migration. Cancer Microenviron 11(2–3):115–124. https://doi.org/10.1007/s12307-018-0215-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Pietzner K, Nasser S, Alavi S, Darb-Esfahani S, Passler M, Muallem MZ, Sehouli J (2018) Checkpoint-inhibition in ovarian cancer: rising star or just a dream? J Gynecol Oncol 29(6):e93. https://doi.org/10.3802/jgo.2018.29.e93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wang S, Li J, Xie J, Liu F, Duan Y, Wu Y, Huang S, He X, Wang Z, Wu X (2018) Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin beta4/SNAI1/SIRT3 signaling pathway. Oncogene 37(30):4164–4180. https://doi.org/10.1038/s41388-018-0252-x

    Article  PubMed  CAS  Google Scholar 

  19. Li J, Chen L, Xiong Y, Zheng X, Xie Q, Zhou Q, Shi L, Wu C, Jiang J, Wang H (2017) Knockdown of PD-L1 in human gastric cancer cells inhibits tumor progression and improves the cytotoxic sensitivity to CIK therapy. Cell Physiol Biochem 41(3):907–920. https://doi.org/10.1159/000460504

    Article  PubMed  CAS  Google Scholar 

  20. Yahata T, Mizoguchi M, Kimura A, Orimo T, Toujima S, Kuninaka Y, Nosaka M, Ishida Y, Sasaki I, Fukuda-Ohta Y, Hemmi H, Iwahashi N, Noguchi T, Kaisho T, Kondo T, Ino K (2019) Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cancer progression. Cancer Sci 110(4):1279–1292. https://doi.org/10.1111/cas.13958

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Christofori G (2006) New signals from the invasive front. Nature 441(7092):444–450. https://doi.org/10.1038/nature04872

    Article  PubMed  CAS  Google Scholar 

  22. Torre LA, Islami F, Siegel RL, Ward EM, Jemal A (2017) global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev 26(4):444–457. https://doi.org/10.1158/1055-9965.EPI-16-0858

    Article  PubMed  Google Scholar 

  23. Moffitt L, Karimnia N, Stephens A, Bilandzic M (2019) Therapeutic targeting of collective invasion in ovarian cancer. Int J Mol Sci. https://doi.org/10.3390/ijms20061466

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yasukawa M, Liu Y, Hu L, Cogdell D, Gharpure KM, Pradeep S, Nagaraja AS, Sood AK, Zhang W (2017) ADAMTS16 mutations sensitize ovarian cancer cells to platinum-based chemotherapy. Oncotarget 8(51):88410–88420. https://doi.org/10.18632/oncotarget.11120

    Article  PubMed  Google Scholar 

  25. Blomberg OS, Spagnuolo L, de Visser KE (2018) Immune regulation of metastasis: mechanistic insights and therapeutic opportunities. Dis Model Mech. https://doi.org/10.1242/dmm.036236

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Ueda R, Iwata-Kajihara T, Nishio H, Kawamura N, Kawakami Y (2011) The mechanisms of cancer immunoescape and development of overcoming strategies. Int J Hematol 93(3):294–300. https://doi.org/10.1007/s12185-011-0799-6

    Article  PubMed  Google Scholar 

  27. Meng Y, Liang H, Hu J, Liu S, Hao X, Wong MSK, Li X, Hu L (2018) PD-L1 expression correlates with tumor infiltrating lymphocytes and response to neoadjuvant chemotherapy in cervical cancer. J Cancer 9(16):2938–2945. https://doi.org/10.7150/jca.22532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Cai Z, Yang F, Yu L, Yu Z, Jiang L, Wang Q, Yang Y, Wang L, Cao X, Wang J (2012) Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol 188(12):5954–5961. https://doi.org/10.4049/jimmunol.1103466

    Article  PubMed  CAS  Google Scholar 

  29. Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Can Res 65(10):3967–3979. https://doi.org/10.1158/0008-5472.CAN-04-2427

    Article  CAS  Google Scholar 

  30. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423):841–844. https://doi.org/10.1038/362841a0

    Article  PubMed  CAS  Google Scholar 

  31. Guo H, Zhu Q, Yu X, Merugu SB, Mangukiya HB, Smith N, Li Z, Zhang B, Negi H, Rong R, Cheng K, Wu Z, Li D (2017) Tumor-secreted anterior gradient-2 binds to VEGF and FGF2 and enhances their activities by promoting their homodimerization. Oncogene 36(36):5098–5109. https://doi.org/10.1038/onc.2017.132

    Article  PubMed  CAS  Google Scholar 

  32. Khochenkov DA, Solomko ES, Peretolchina NM, Ryabaya OO, Stepanova EV (2015) Antiangiogenic activity of alofanib, an allosteric inhibitor of fibroblast growth factor receptor 2. Bull Exp Biol Med 160(1):84–87. https://doi.org/10.1007/s10517-015-3104-5

    Article  PubMed  CAS  Google Scholar 

  33. Zamarron BF, Chen W (2011) Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 7(5):651–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741. https://doi.org/10.1158/1078-0432.CCR-07-4843

    Article  PubMed  CAS  Google Scholar 

  35. Inoue K, Slaton JW, Eve BY, Kim SJ, Perrotte P, Balbay MD, Yano S, Bar-Eli M, Radinsky R, Pettaway CA, Dinney CP (2000) Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 6(5):2104–2119

    PubMed  CAS  Google Scholar 

  36. Zhou J, Ye F, Chen H, Lv W, Gan N (2007) The expression of interleukin-10 in patients with primary ovarian epithelial carcinoma and in ovarian carcinoma cell lines. J Int Med Res 35(3):290–300. https://doi.org/10.1177/147323000703500302

    Article  PubMed  CAS  Google Scholar 

  37. Sheikhpour E, Noorbakhsh P, Foroughi E, Farahnak S, Nasiri R, Neamatzadeh H (2018) A survey on the role of interleukin-10 in breast cancer: a narrative. Rep Biochem Mol Biol 7(1):30–37

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Kim S, Lee J, Jeon M, Lee JE, Nam SJ (2016) MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells. Tumour Biol 37(4):4991–4999. https://doi.org/10.1007/s13277-015-4345-7

    Article  PubMed  CAS  Google Scholar 

  39. Qiu XY, Hu DX, Chen WQ, Chen RQ, Qian SR, Li CY, Li YJ, Xiong XX, Liu D, Pan F, Yu SB (1864) Chen XQ (2018) PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation. Biochim Biophys Acta Mol Basis Dis 5:1754–1769. https://doi.org/10.1016/j.bbadis.2018.03.002

    Article  CAS  Google Scholar 

  40. Wang Y, Wang H, Zhao Q, Xia Y, Hu X, Guo J (2015) PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med Oncol 32(8):212. https://doi.org/10.1007/s12032-015-0655-2

    Article  PubMed  CAS  Google Scholar 

  41. Liao Y, Chen L, Feng Y, Shen J, Gao Y, Cote G, Choy E, Harmon D, Mankin H, Hornicek F, Duan Z (2017) Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells. Oncotarget 8(18):30276–30287. https://doi.org/10.18632/oncotarget.16326

    Article  PubMed  PubMed Central  Google Scholar 

  42. Qu QX, Xie F, Huang Q, Zhang XG (2017) Membranous and cytoplasmic expression of PD-L1 in ovarian cancer cells. Cell Physiol Biochem 43(5):1893–1906. https://doi.org/10.1159/000484109

    Article  PubMed  CAS  Google Scholar 

  43. Mailloux AW, Young MR (2010) Regulatory T-cell trafficking: from thymic development to tumor-induced immune suppression. Crit Rev Immunol 30(5):435–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shi C, Chen Y, Chen Y, Yang Y, Bing W, Qi J (2019) CD4(+) CD25(+) regulatory T cells promote hepatocellular carcinoma invasion via TGF-beta1-induced epithelial-mesenchymal transition. Onco Targets Ther 12:279–289. https://doi.org/10.2147/OTT.S172417

    Article  PubMed  CAS  Google Scholar 

  45. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, Wang HY, Cheng SQ, Xie D, Wang XF (2012) TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 22(3):291–303. https://doi.org/10.1016/j.ccr.2012.07.023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Barnett JC, Bean SM, Whitaker RS, Kondoh E, Baba T, Fujii S, Marks JR, Dressman HK, Murphy SK, Berchuck A (2010) Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype. Gynecol Oncol 116(3):556–562. https://doi.org/10.1016/j.ygyno.2009.11.020

    Article  PubMed  CAS  Google Scholar 

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Funding

The work was funded by the Research Fund from the Department of Obstetrics and Gynaecology, the University of Hong Kong.

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  1. Jing-Jing Wang and Michelle Kwan-Yee Siu have contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China

    Jing-Jing Wang, Michelle Kwan-Yee Siu, Yu-Xin Jiang, David Wai Chan, Hextan Yuen-Sheung Ngan & Karen Kar-Loen Chan

  2. Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region of China

    Annie Nga-Yin Cheung

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  1. Jing-Jing Wang
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Correspondence to Karen Kar-Loen Chan.

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Wang, JJ., Siu, M.KY., Jiang, YX. et al. Infiltration of T cells promotes the metastasis of ovarian cancer cells via the modulation of metastasis-related genes and PD-L1 expression. Cancer Immunol Immunother 69, 2275–2289 (2020). https://doi.org/10.1007/s00262-020-02621-9

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