Impact of IL-12 and IL-18 Combined Stimulation on INF-γ and TNF-α Production by PBMCs Derived from Egyptian Ovarian Cancer Patients

ORIGINAL ARTICLE
Nourhan E. Mohamed, Noha A. Mahana, Abeer Mahmoud Badr, Ola S. Ahmed, Ahmed M. Lymona, Sarah S. Nasr, Auhood Nassar

 
For citation: Mohamed NE, Mahana NA, Badr AM, Ahmed OS, Lymona AM, Nasr SS, Nassar A. Impact of IL-12 and IL-18 Combined Stimulation on INF-γ and TNF-α Production by PBMCs Derived from Egyptian Ovarian Cancer Patients. International Journal of Biomedicine. 2024;14(3):435-440. doi:10.21103/Article14(3)_OA7
 
Originally published September 6, 2024

Abstract: 

Background: Cytokines play a crucial role in modulating the immune cells' response to tumors. Utilizing IL-18 and IL-12 as immunotherapeutic agents has gained much attention for cancer treatment. This study aimed to investigate the effect of combined stimulation with IL-12 and IL-18 on the ability of peripheral blood mononuclear cells (PBMCs) derived from Egyptian ovarian cancer (OC) patients to produce IFN-γ and TNF-α. 
Methods and Results: This in vitro study included 8 patients with benign ovarian tumors, 8 patients with low-grade OC, and 8 patients with high-grade OC. PBMCs were stimulated with IL-12 (10ng/ml) and IL-18 (50ng/ml) for 7 days. The levels of IFN-γ and TNF-α were quantified before and after stimulation by quantitative sandwich ELISA. Stimulated PBMCs isolated from patients with low-grade OC showed good ability to produce high levels of IFN-γ, while stimulated PBMCs isolated from patients with high-grade OC patients showed good and high production of TNF-α.
Conclusion: We found that the combined stimulation with IL-12 and IL-18 significantly enhances the production of IFN-γ and TNF-α by PBMCs in OC patients, suggesting a potential avenue for cancer immunotherapy.

Keywords: 
ovarian cancer • IFN-γ • IL-12 • IL-18 • peripheral blood mononuclear cells • TNF-α
References: 
  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum in: CA Cancer J Clin. 2020 Jul;70(4):313. doi: 10.3322/caac.21609. PMID: 30207593.
  2. Coburn SB, Bray F, Sherman ME, Trabert B. International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. Int J Cancer. 2017 Jun 1;140(11):2451-2460. doi: 10.1002/ijc.30676. Epub 2017 Mar 21. PMID: 28257597; PMCID: PMC5595147.
  3. Yoneda A, Lendorf ME, Couchman JR, Multhaupt HA. Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans. J Histochem Cytochem. 2012 Jan;60(1):9-21. doi: 10.1369/0022155411428469. PMID: 22205677; PMCID: PMC3283135.
  4. Jacobs IJ, Menon U. Progress and challenges in screening for early detection of ovarian cancer. Mol Cell Proteomics. 2004 Apr;3(4):355-66. doi: 10.1074/mcp.R400006-MCP200. Epub 2004 Feb 5. PMID: 14764655.
  5. Badgwell D, Bast RC Jr. Early detection of ovarian cancer. Dis Markers. 2007;23(5-6):397-410. doi: 10.1155/2007/309382. PMID: 18057523; PMCID: PMC3851959.
  6. Hunn J, Rodriguez GC. Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol. 2012 Mar;55(1):3-23. doi: 10.1097/GRF.0b013e31824b4611. PMID: 22343225.
  7. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018 Jul;68(4):284-296. doi: 10.3322/caac.21456. Epub 2018 May 29. PMID: 29809280; PMCID: PMC6621554.
  8. Chornokur G, Amankwah EK, Schildkraut JM, Phelan CM. Global ovarian cancer health disparities. Gynecol Oncol. 2013 Apr;129(1):258-64. doi: 10.1016/j.ygyno.2012.12.016. Epub 2012 Dec 22. PMID: 23266352; PMCID: PMC3608795.
  9. Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971. doi: 10.1155/2014/437971. Epub 2014 Sep 21. PMID: 25328522; PMCID: PMC4189936.
  10. Samadi M, Kamrani A, Nasiri H, Shomali N, Heris JA, Shahabi P, Ghahremanzadeh K, Mohammadinasab R, Sadeghi M, Sadeghvand S, Shotorbani SS, Akbari M. Cancer immunotherapy focusing on the role of interleukins: A comprehensive and updated study. Pathol Res Pract. 2023 Sep;249:154732. doi: 10.1016/j.prp.2023.154732. Epub 2023 Aug 1. PMID: 37567033.
  11. Yasuda K, Nakanishi K, Tsutsui H. Interleukin-18 in Health and Disease. Int J Mol Sci. 2019 Feb 2;20(3):649. doi: 10.3390/ijms20030649. PMID: 30717382; PMCID: PMC6387150.
  12. Liu J, Cao S, Kim S, Chung EY, Homma Y, Guan X, Jimenez V, Ma X. Interleukin-12: an update on its immunological activities, signaling and regulation of gene expression. Curr Immunol Rev. 2005 Jun;1(2):119-137. doi: 10.2174/1573395054065115. PMID: 21037949; PMCID: PMC2965603.
  13. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423-74. doi: 10.1146/annurev.immunol.19.1.423. PMID: 11244043.
  14. Mendoza JL, Escalante NK, Jude KM, Sotolongo Bellon J, Su L, Horton TM, Tsutsumi N, Berardinelli SJ, Haltiwanger RS, Piehler J, Engleman EG, Garcia KC. Structure of the IFNγ receptor complex guides design of biased agonists. Nature. 2019 Mar;567(7746):56-60. doi: 10.1038/s41586-019-0988-7. Epub 2019 Feb 27. PMID: 30814731; PMCID: PMC6561087.
  15. Burke JD, Young HA. IFN-γ: A cytokine at the right time, is in the right place. Semin Immunol. 2019 Jun;43:101280. doi: 10.1016/j.smim.2019.05.002. Epub 2019 Jun 17. PMID: 31221552; PMCID: PMC7367502.
  16. Kannan Y, Yu J, Raices RM, Seshadri S, Wei M, Caligiuri MA, Wewers MD. IκBζ augments IL-12- and IL-18-mediated IFN-γ production in human NK cells. Blood. 2011 Mar 10;117(10):2855-63. doi: 10.1182/blood-2010-07-294702. Epub 2011 Jan 11. PMID: 21224476; PMCID: PMC3062297.
  17. Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006 Sep;25(3):409-16. doi: 10.1007/s10555-006-9005-3. PMID: 16951987.
  18. Nowak M, Klink M, Glowacka E, Sulowska Z, Kulig A, Szpakowski M, Szyllo K, Tchorzewski H. Production of cytokines during interaction of peripheral blood mononuclear cells with autologous ovarian cancer cells or benign ovarian tumour cells. Scand J Immunol. 2010 Feb;71(2):91-8. doi: 10.1111/j.1365-3083.2009.02350.x. PMID: 20384860.
  19. Fehniger TA, Shah MH, Turner MJ, VanDeusen JB, Whitman SP, Cooper MA, Suzuki K, Wechser M, Goodsaid F, Caligiuri MA. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol. 1999 Apr 15;162(8):4511-20. PMID: 10201989.
  20. Corthay A, Skovseth DK, Lundin KU, Røsjø E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B. Primary antitumor immune response mediated by CD4+ T cells. Immunity. 2005 Mar;22(3):371-83. doi: 10.1016/j.immuni.2005.02.003. PMID: 15780993.
  21. Wall L, Burke F, Smyth JF, Balkwill F. The anti-proliferative activity of interferon-gamma on ovarian cancer: in vitro and in vivo. Gynecol Oncol. 2003 Jan;88(1 Pt 2):S149-51. doi: 10.1006/gyno.2002.6707. PMID: 12586108.
  22. Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006 Sep;25(3):435-57. doi: 10.1007/s10555-006-9006-2. PMID: 16951986.
  23. Marth C, Fiegl H, Zeimet AG, Müller-Holzner E, Deibl M, Doppler W, Daxenbichler G. Interferon-gamma expression is an independent prognostic factor in ovarian cancer. Am J Obstet Gynecol. 2004 Nov;191(5):1598-605. doi: 10.1016/j.ajog.2004.05.007. PMID: 15547530.
  24. Yamamura M, Kawashima M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, Morita Y, Ohmoto Y, Makino H. Interferon-gamma-inducing activity of interleukin-18 in the joint with rheumatoid arthritis. Arthritis Rheum. 2001 Feb;44(2):275-85. doi: 10.1002/1529-0131(200102)44:2<275::AID-ANR44>3.0.CO;2-B. PMID: 11229457.
  25. Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei XQ, Xu D, Field M, Foulis A, Liew FY, McInnes IB. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999 Nov;104(10):1393-401. doi: 10.1172/JCI7317. PMID: 10562301; PMCID: PMC409841.
  26. Shiratori I, Suzuki Y, Oshiumi H, Begum NA, Ebihara T, Matsumoto M, Hazeki K, Kodama K, Kashiwazaki Y, Seya T. Recombinant interleukin-12 and interleukin-18 antitumor therapy in a guinea-pig hepatoma cell implant model. Cancer Sci. 2007 Dec;98(12):1936-42. doi: 10.1111/j.1349-7006.2007.00614.x. Epub 2007 Sep 19. PMID: 17888032.
  27. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, Neal CC, Yu L, Oh ST, Lee YS, Mulder A, Claas F, Cooper MA, Fehniger TA. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 2016 Sep 21;8(357):357ra123. doi: 10.1126/scitranslmed.aaf2341. PMID: 27655849; PMCID: PMC5436500.
  28. Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med. 2012 Dec 17;209(13):2351-65. doi: 10.1084/jem.20120944. Epub 2012 Dec 3. PMID: 23209317; PMCID: PMC3526364.
  29. Kawashima M, Miossec P. Decreased response to IL-12 and IL-18 of peripheral blood cells in rheumatoid arthritis. Arthritis Res Ther. 2004;6(1):R39-R45. doi: 10.1186/ar1020. Epub 2003 Nov 4. PMID: 14979936; PMCID: PMC400411.
  30. Glezerman M, Mazot M, Maymon E, Piura B, Prinsloo I, Benharroch D, Yanai-Inbar I, Huleihel M. Tumor necrosis factor-alpha and interleukin-6 are differently expressed by fresh human cancerous ovarian tissue and primary cell lines. Eur Cytokine Netw. 1998 Jun;9(2):171-9. PMID: 9681393.
  31. Daraï E, Detchev R, Hugol D, Quang NT. Serum and cyst fluid levels of interleukin (IL) -6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Hum Reprod. 2003 Aug;18(8):1681-5. doi: 10.1093/humrep/deg321. PMID: 12871882.
  32. Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006 Sep;25(3):409-16. doi: 10.1007/s10555-006-9005-3. PMID: 16951987.

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Received June 13, 2024.
Accepted August 30, 2024.
©2024 International Medical Research and Development Corporation.