Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma

Pan,Xiu-Cheng; Li,Li; Mao,Juan-Juan; Yao,Wei; Zheng,Jun-Nian; Liu,Mei; Fu,Juan-Juan

doi:10.3892/ol.2012.966

Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma

Authors:
- Xiu-Cheng Pan
- Li Li
- Juan-Juan Mao
- Wei Yao
- Jun-Nian Zheng
- Mei Liu
- Juan-Juan Fu
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Affiliations: Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, P.R. China, Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, P.R. China
Published online on: October 12, 2012 https://doi.org/10.3892/ol.2012.966
Pages: 90-96

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Abstract

Cancer immunotherapies are designed to elicit T-cell responses that inhibit tumor growth. Previous studies have demonstrated that interleukin 21 (IL-21) is a promising cytokine for cancer immunotherapy due to its ability to induce the immunity of T cells and natural killer cells, whereas blockade of the interaction of programmed death receptor-1 (PD-1) with its ligand (PD-L1) reduces peripheral tolerance. In the current study, we investigated IL-21 alone and in combination with soluble PD-1 (sPD-1) for the treatment of experimental H22 murine hepatocarcinoma. The naked plasmids pmIL-21 and/or psPD-1 were used for local gene transfer by injection. In these assays, sPD-1 combined with IL-21 was found to significantly inhibit the growth of the tumors in mice. Combined treatment with IL-21 and sPD-1 enhanced the antitumor immune response compared with that induced by IL-21 alone. Combined treatment was found to increase CTL cytotoxicity, increase the number of CTLs and NK cells in splenocytes, upregulate the cytokines IFN-γ and IL-2 and downregulate IL-10. Thus, immunotherapy with IL-21 in combination with sPD-1 was found to induce a more efficacious antitumor immune response, which may have potential clinical implications.

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1	Parrish-Novak J, Dillon SR, Nelson A, et al: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 408:57–63. 2000. View Article : Google Scholar : PubMed/NCBI
2	Bryant VL, Ma CS, Avery DT, Li Y, Good KL, Corcoran LM, de Waal Malefyt R and Tangye SG: Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5⁺T follicular helper cells. J Immunol. 179:8180–8190. 2007. View Article : Google Scholar : PubMed/NCBI
3	Kashiwakuma D, Suto A, Hiramatsu Y, Ikeda K, Takatori H, Suzuki K, Kaqami S, Hirose K, Watanabe N, Iwamoto I and Nakajima H: B and T lymphocyte attenuator suppresses IL-21 production from follicular Th cells and subsequent humoral immune responses. J Immunol. 185:2730–2736. 2010. View Article : Google Scholar : PubMed/NCBI
4	Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ and Godfrey DI: IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol. 178:2827–2834. 2007. View Article : Google Scholar : PubMed/NCBI
5	Jin H, Carrio R, Yu A and Malek TR: Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol. 173:657–665. 2004. View Article : Google Scholar : PubMed/NCBI
6	Brandt K, Bulfone-Paus S, Foster DC and Rückert R: Interleukin-21 inhibits dendritic cell activation and maturation. Blood. 102:4090–4098. 2003. View Article : Google Scholar : PubMed/NCBI
7	Distler JH, Jüngel A, Kowal-Bielecka O, et al: Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis. Arthritis Rheum. 52:856–864. 2005. View Article : Google Scholar : PubMed/NCBI
8	Caruso R, Fina D, Peluso I, Stolfi C, Fantini MC, Gioia V, Caprioli F, Del Vecchio Bianco G, Paoluzi OA, Macdonald TT, et al: A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. Gastroenterology. 132:166–175. 2007. View Article : Google Scholar : PubMed/NCBI
9	Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF Jr, Cheever AW, Young DA, Collins M, Grusby MJ and Wynn TA: The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest. 116:2044–2055. 2006. View Article : Google Scholar : PubMed/NCBI
10	Di Carlo E, Comes EA, Orengo AM, Rosso O, Meazza R, Musiani P, Colombo MP and Ferrini S: IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice. J Immunol. 172:1540–1547. 2004.PubMed/NCBI
11	Dou J, Chen GB, Wang J, Zhao FS, Chen JS, Fang XS, Tang Q and Chu LL: Preliminary study on mouse interleukin-21 application in tumor gene therapy. Cell Mol Immunol. 1:461–466. 2004.PubMed/NCBI
12	Moroz A, Eppolito C, Li Q, Tao JM, Clegg CH and 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. 173:900–909. 2004.PubMed/NCBI
13	Liu S, Lizée G, Lou Y, Liu CW, Overwijk WW, Wang G and Hwu P: IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells. Int Immunol. 19:1213–1221. 2007. View Article : Google Scholar : PubMed/NCBI
14	Casey KA and Mescher MF: IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype. J Immunol. 178:7640–7648. 2007. View Article : Google Scholar : PubMed/NCBI
15	Kim-Schulze S, Kim HS, Fan Q, Kim DW and Kaufman HL: Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment. Mol Ther. 17:380–388. 2009. View Article : Google Scholar : PubMed/NCBI
16	Wang G, Tschoi M, Spolski R, Lou YY, Ozaki K, Feng C, Kim G, Leonard WJ and Hwu P: In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 63:9016–9022. 2003.PubMed/NCBI
17	Schmidt H, Brown J, Mouritzen U, Selby P, Fode K, Svane IM, Cook GP, Mollerup DH and Geertsen PF: Safety and clinical effect of subcutaneous human interleukin-21 in patients with metastatic melanoma or renal cell carcinoma: a phase I trial. Clin Cancer Res. 16:5312–5319. 2010. View Article : Google Scholar : PubMed/NCBI
18	Grünwald V, Desar IM, Haanen J, Fiedler W, Mouritzen U, Olsen MW and van Herpen CM: A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC). Acta Oncol. 50:121–126. 2011.PubMed/NCBI
19	Hashmi MH and Van Veldhuizen PJ: Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin’s lymphoma. Expert Opin Biol Ther. 5:807–817. 2010.PubMed/NCBI
20	Dong H, Strome SE and Salomao DR: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 8:793–800. 2002. View Article : Google Scholar : PubMed/NCBI
21	Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y and Fan J: Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 15:971–979. 2009. View Article : Google Scholar : PubMed/NCBI
22	Butte MJ, Keir ME, Phamduy TB, Sharpe AH and Freeman GJ: Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 27:111–122. 2007. View Article : Google Scholar : PubMed/NCBI
23	Iwai Y, Terawaki S and Honjo T: PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 17:133–144. 2005. View Article : Google Scholar : PubMed/NCBI
24	Wang W, Lau R, Yu D, Zhu WW, Korman A and Weber J: PD-1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4⁺ CD25 (Hi) regulatory T cells. Int Immunol. 21:1065–1077. 2009. View Article : Google Scholar : PubMed/NCBI
25	Onlamoon N, Rogers K, Mayne AE, Pattanapanyasat K, Mori K, Villinger F and Ansari AA: Soluble PD-1 rescues the proliferative response of simian immunodeficiency virus-specific CD4 and CD8 T cells during chronic infection. Immunology. 124:277–293. 2008. View Article : Google Scholar : PubMed/NCBI
26	Wang XH, Zhang GM, He YF, Zhang H and Feng ZH: Soluble PD-1 can augment anti-tumor immunity induced by HSP70-peptide complex in tumor bearing mice. Chin J Cell Mol Immunol. 20:655–658. 2004.(In Chinese).
27	He YF, Zhang GM, Wang XH, Zhang H, Yuan Y, Li D and Feng ZH: Eukaryotic expression and functional characterization of PD-1 extracellular domain. Chin J Biotechnol. 20:699–703. 2004.(In Chinese).
28	Dou J, Wang Y, Wang J, Zhao F, Li Y, Cao M, et al: Antitumor efficacy induced by human ovarian cancer cells secreting IL-21 alone or combination with GM-CSF cytokines in nude mice model. Immunobiolog. 214:483–492. 2009. View Article : Google Scholar : PubMed/NCBI
29	Jauch D, Martin M, Schiechl G, Kesselring R, Schlitt HJ, Geissler EK and Fichtner-Feigl S: Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice. Gut. 60:1678–1686. 2011. View Article : Google Scholar : PubMed/NCBI
30	Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA and Fauci AS: The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 181:6738–6746. 2008.
31	Arens R and Schoenberger SP: Plasticity in programming of effector and memory CD8 T-cell formation. Immunol Rev. 235:190–205. 2010.PubMed/NCBI
32	Cerwenka A and Lanier LL: Natural killer cells, viruses and cancer. Nat Rev Immunol. 1:41–49. 2001. View Article : Google Scholar : PubMed/NCBI
33	Smyth MJ, Hayakawa Y, Takeda K and Yagita H: New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer. 2:850–861. 2002. View Article : Google Scholar : PubMed/NCBI
34	O’Garra A and Arai N: The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol. 10:542–550. 2000.PubMed/NCBI