Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
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Index Copernicus  – 171.00; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 5, May, p. 583–589

doi: 10.17219/acem/68703

Publication type: original article

Language: English

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Interleukin 21 treatment in a murine model as a novel potential cytokine immunotherapy for colon cancer

Chen Chen1,A,B,C,D,E,F, Xiaoning Liu2,A,B,C,F, Yi Ren3,A,B,F

1 Clinical School, Hubei University of Chinese Medicine, China

2 Central Laboratory of Huai’an First People’s Hospital, Nanjing Medical University, China

3 Department of Breast and Thyroid Surgery, Huai’an First People Hospital, Nanjing Medical University, China

Abstract

Background. Interleukin 21 (IL-21), which belongs to the common γ-chain (γc) family, is a novel tumor suppressor that has been shown to affect T-cell proliferation, survival and function. However, the role of IL-21 in colon cancer remains unclear.
Objectives. We sought to determine whether IL-21 could inhibit the progression of colon cancer in mice; we also explored the mechanisms underlying the immunological effects of IL-21 in colon cancer.
Material and Methods. Exogenous IL-21 protein was expressed to treat tumor-bearing mice and the production of cytokine interleukin 4, interferon gamma and lambda from CD4+ T, CD8+ T, and NK cells were measured, along with the survival times of these tumor-bearing mice.
Results. Interleukin 21 promoted the secretion of interferon gamma from the CD4+ T, CD8+ T and NK cells and it enhanced the production of interferon lambda by the NK cells. More importantly, IL-21 treatment significantly enhanced antitumor effects in favor of tumor eradication. We also found that CD8+ T and NK cells are necessary for the antitumor immune responses elicited by IL-21.
Conclusion. Interleukin 21 is a powerful tool for activating CD8+ T cells and NK cells which exhibit potent cytolytic effector functions and should therefore be exploited for anticancer immunotherapy. Our findings support the development of a novel cytokine immunotherapy against colon cancer.

Key words

colon cancer, immunotherapy, interleukin 21, interferon γ

References (29)

  1. Zheng ZX, Zheng RS, Zhang SW, Chen WQ. Colorectal cancer incidence and mortality in China, 2010. Asian Pac J Cancer Prev. 2014;15: 8455–8460.
  2. Liu S, Zheng R, Zhang M, Zhang S, Sun X, Chen W. Incidence and mortality of colorectal cancer in China, 2011. Chin J Cancer Res. 2015;27:
  3. Chen W, Zheng R, Zeng H, Zhang S. The updated incidences and mortalities of major cancers in China, 2011. Chin J Cancer. 2015;34:53.
  4. Guend H, Patel S, Nash GM. Abdominal metastases from colorectal cancer: Intraperitoneal therapy. J Gastrointest Oncol. 2015;6:693–698.
  5. Chibaudel B, Tournigand C, Bonnetain F, et al. Therapeutic strategy in unresectable metastatic colorectal cancer: An up-dated review. Ther Adv Med Oncol. 2015;7:153–169.
  6. Santegoets SJ, Turksma AW, Powell JDJ, Hooijberg E, de Gruijl TD. IL-21 in cancer immunotherapy: At the right place at the right time. Oncoimmunology. 2013;2:e24522.
  7. Leung J, Suh WK. The CD28-B7 family in anti-tumor immunity: Emerging concepts in cancer immunotherapy. Immune Netw. 2014;14: 265–276.
  8. Phan GQ, Rosenberg SA. Adoptive cell transfer for patients with metastatic melanoma: The potential and promise of cancer immunotherapy. Cancer Control. 2013;20:289–297.
  9. Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity. 2013;39:49–60.
  10. Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: Comparative evaluation of IL-2, IL-15, and IL-21. J Immunol. 2004; 173:900–909.
  11. Kumano M, Hara I, Furukawa J, et al. Interleukin-21 activates cytotoxic T lymphocytes and natural killer cells to generate antitumor response in mouse renal cell carcinoma. J Urol. 2007;178:1504–1509.
  12. Ozaki K, Spolski R, Feng CG, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298:1630–1634.
  13. Croce M, Rigo V, Ferrini S. IL-21: A pleiotropic cytokine with potential applications in oncology. J Immunol Res. 2015;2015:696578.
  14. Li J, Shen W, Kong K, Liu Z. Interleukin-21 induces T-cell activation and proinflammatory cytokine secretion in rheumatoid arthritis. Scand J Immunol. 2006;64:515–522.
  15. Santegoets SJ, Turksma AW, Suhoski MM, et al. IL-21 promotes the expansion of CD27+ CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells. J Transl Med. 2013;11:37.
  16. Spolski R, Leonard WJ. Interleukin-21: A double-edged sword with therapeutic potential. Nat Rev Drug Discov. 2014;13:379–395.
  17. Zhou L, Li JL, Zhou Y, et al. Induction of interferon-λ contributes to TLR3 and RIG-I activation-mediated inhibition of herpes simplex virus type 2 replication in human cervical epithelial cells. Mol Hum Reprod. 2015;21:917–929.
  18. Ugai S, Shimozato O, Kawamura K, et al. Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. Cancer Gene Ther. 2003;10:187–192.
  19. Park YK, Shin DJ, Cho D, et al. Interleukin-21 increases direct cytotoxicity and IFN-gamma production of ex vivo expanded NK cells towards breast cancer cells. Anticancer Res. 2012;32:839–846.
  20. Green J, Ariyan C. Update on immunotherapy in melanoma. Surg Oncol Clin N Am. 2015;24:337–346.
  21. Curti BD. Immunomodulatory and antitumor effects of interleukin-21 in patients with renal cell carcinoma. Expert Rev Anticancer Ther. 2006;6:905–909.
  22. Roda JM, Parihar R, Lehman A, Mani A, Tridandapani S, Carson WE 3rd. Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J Immunol. 2006;177:120–129.
  23. White L, Krishnan S, Strbo N, et al. Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood. 2007;109:3873–3880.
  24. Zeng R, Spolski R, Finkelstein SE, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med. 2005;201: 139–148.
  25. Sato A, Ohtsuki M, Hata M, Kobayashi E, Murakami T. Antitumor activity of IFN-lambda in murine tumor models. J Immunol. 2006;176:7686–7694.
  26. Brahmer JR, Tykodi SS, Chow L, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366: 2455–2465.
  27. Eroglu Z, Kim DW, Wang X, et al. Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab. Eur J Cancer. 2015;51:2689–2697.
  28. Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is as-sociated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207:2175–2186.
  29. Tangye SG. Advances in IL-21 biology – enhancing our understanding of human disease. Curr Opin Immunol. 2015;34:107–115.