Inhibitory Effect of iAPA-DC/CTL on SMMC-7721 Xenograft in Nude Mice_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 FUHai-feng ^1,2,3 , DINGYou-ming ¹ , ZHOUWen-bo ² , WEIYing ⁴ , WUHong-wei ² , WANGBin ¹ , XUJun-hui ¹ , XUYan-zhe ¹

1. Department of Hepatobiliary and Laparoscopic Surgery, People's Hospital of Wuhan University, Wuhan 430060, Hubei Province, China;
2. Department of Hepatobiliary Surgery, Dongfeng Hospital, Hubei University of Medicine, Shiyan 442008, Hubei Province, China;
3. Department of General Surgery, Maojian Hospital, Dongfeng Motor Corporation, Shiyan 442012, Hubei Province, China;
4. Department of Experimental Center, Dongfeng Hospital, Hubei University of Medicine, Shiyan 442008, Hubei Province, China;

Corresponding?author：

DINGYou-ming, Email: ; ZHOUWen-bo, Email:

Keywords：

Hepatocellular carcinoma; Inhibition of antigen-presentation attenuators; Dendritic cell; Cytotoxic T lymphocyte

DOI：

10.7507/1007-9424.20150108

Video：

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Objective To investigate the inhibitory effect of the inhibition of antigen-presentation attenuators (iAPA)-based dendritic cells (DC) and cytotoxic T lymphocytes (CTL)-iAPA-DC/CTL on SMMC-7721 xenograft in nude mice. Methods Using the human hepatic carcinoma cell line SMMC-7721 on nude mice to establish a transplanted tumor model of human hepatocellular carcinoma (HCC).Twelve nude mice were divided into two groups randomly: normal saline control group (control group) and iAPA-DC/CTL group (n=6, each).After four times treatment with iAPA-DC/CTL (once a week), all mice were sacrificed.Tumor growth was calculated by measuring the long/short diameters and the tumor growth curve was delineated.The tumors were weighed and the tumor inhibition rate was calculated.In addition, the histopathological examination was conducted. Results The SMMC-7721 xenograft model was successfully established in 85.71% (12/14) of all mice.The tumor volume was (3 661.48±322.59) mm³ and (2 725.36±252.65) mm³ in control group and iAPA-DC/CTL group, respectively.The tumor growth was significantly inhibited in iAPA-DC/CTL group (t=5.62, P < 0.05).The tumor weight was (1.97±0.21) g and (1.38±0.14) g in control group and iAPA-DC/CTL group, respectively.The tumor weight in iAPA-DC/CTL group was significantly reduced (t=5.73, P < 0.05), and the tumor inhibition rate was 29.95%.After immunohistochemical staining T lymphocyte counts was 0 cell/HPF and (54.24±4.31) cells/HPF in control group and iAPA-DC/CTL group, respectively.The number of T lymphocytes in iAPA-DC/CTL group was significantly increased (t=25.02, P < 0.05). Conclusion iAPA-DC/CTL could effectively inhibit the growth of subcutaneously implanted HCC.

Citation： FUHai-feng, DINGYou-ming, ZHOUWen-bo, WEIYing, WUHong-wei, WANGBin, XUJun-hui, XUYan-zhe. Inhibitory Effect of iAPA-DC/CTL on SMMC-7721 Xenograft in Nude Mice. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(4): 399-403. doi: 10.7507/1007-9424.20150108 Copy

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2.	唐耘天, 唐步堅.原發性肝癌免疫治療的研究進展.中國癌癥防治雜志, 2013, 5(1):79-82.
3.	Ueda Y, Itoh T, Fuji N, et al.Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy.Cancer Immunol Immunother, 2007, 56(3):381-389.
4.	Hong B, Ren W, Song XT, et al.Human suppressor of cytokine signaling 1 controls immunostimulatory activity of monocyte-derived dendritic cells.Cancer Res, 2009, 69(20):8076-8084.
5.	Udagawa M, Kudo-Saito C, Hasegawa G, et al.Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation.Clin Cancer Res, 2006, 12(24):7465-7475.
6.	劉業六, 錢海鑫, 張逖, 等.趨化因子受體-6小干擾RNA對人肝癌HCCLM6細胞裸鼠皮下移植瘤的抑制作用.中華實驗外科雜志, 2013, 30(12):2577-2579, F3.
7.	周明利, 張樹友.Survivin基因在腫瘤中的作用研究進展.中國普外基礎與臨床雜志, 2011, 18(7):779-782.
8.	Wu JM, Lin XF, Huang ZM, et al.Construction of the HBV S-ecdCD40L fusion gene and effects of HBV S-ecdCD40L modification on function of dendritic cells.J Viral Hepat, 2011, 18(10):e461-e467.
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13.	Palucka AK, Ueno H, Fay J, et al.Dendritic cells:a critical player in cancer therapy?.J Immunother.2008, 31(9):793-805.
14.	宋海峰, 周軍, 潘科, 等.抑制SOCS1聯合OK-432刺激的DC疫苗抗腫效應的初步研究.癌癥.2008, 27(7):685-691.
15.	Quah BJ, O'Neill HC.The immunogenicity of dendritic cell-derived exosomes.Blood Cells Mol Dis.2005, 35(2):94-110.
16.	莫世發, 賈乾斌.細胞免疫功能變化與肝癌的關系研究進展.中國普外基礎與臨床雜志, 2012, 19(4):456-458.
17.	Tatsumi T, Takehara T, Yamaguchi S, et al.Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.Hepatology.2007, 45(1):22-30.
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21.	于鴻, 陳陽, 張健, 等.SOCS1-siRNA沉默SOCS1基因表達對臍血樹突狀細胞生物學活性的影響.中國實驗診斷學, 2012, 16(10):1794-1796.
22.	Evel-Kabler K, Song XT, Aldrich M, et al.SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling.J Clin Invest.2006, 116(1):90-100.
23.	Aldrich M, Sanders D, Lapteva N, et al.SOCS1 downregulation in dendritic cells promotes memory T-cell responses.Vaccine.2008, 26(8):1128-1135.
24.	Hashimoto M, Ayada T, Kinjyo I, et al.Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation.Cancer Sci.2009, 100(4):730-736.
25.	Zitzmann K, Brand S, De Toni EN, et al.SOCS1 silencing enhances antitumor activity of typeⅠIFNs by regulating apoptosis in neuro-endocrine tumor cells.Cancer Res.2007, 67(10):5025-5032.
26.	Kobayashi T, Yoshimura A.Keeping DCs awake by putting SOCS1 to sleep.Trends Immunol.2005, 26(4):177-179.
27.	Gilboa E.Knocking the SOCS1 off dendritic cells.Nat Biotechnol.2004, 22(12):1521-1522.

1. Bruix J, Sherman M.Management of hepatocellular carcinoma:an update.Hepatology, 2011, 53(3):1020-1022.
2. 唐耘天, 唐步堅.原發性肝癌免疫治療的研究進展.中國癌癥防治雜志, 2013, 5(1):79-82.
3. Ueda Y, Itoh T, Fuji N, et al.Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy.Cancer Immunol Immunother, 2007, 56(3):381-389.
4. Hong B, Ren W, Song XT, et al.Human suppressor of cytokine signaling 1 controls immunostimulatory activity of monocyte-derived dendritic cells.Cancer Res, 2009, 69(20):8076-8084.
5. Udagawa M, Kudo-Saito C, Hasegawa G, et al.Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation.Clin Cancer Res, 2006, 12(24):7465-7475.
6. 劉業六, 錢海鑫, 張逖, 等.趨化因子受體-6小干擾RNA對人肝癌HCCLM6細胞裸鼠皮下移植瘤的抑制作用.中華實驗外科雜志, 2013, 30(12):2577-2579, F3.
7. 周明利, 張樹友.Survivin基因在腫瘤中的作用研究進展.中國普外基礎與臨床雜志, 2011, 18(7):779-782.
8. Wu JM, Lin XF, Huang ZM, et al.Construction of the HBV S-ecdCD40L fusion gene and effects of HBV S-ecdCD40L modification on function of dendritic cells.J Viral Hepat, 2011, 18(10):e461-e467.
9. 程婷婷, 徐希, 葛杭萍, 等.慢病毒介導的自殺基因對樹突狀細胞的殺傷作用.醫學研究雜志, 2014, 43(4):71-75.
10. 曹雪濤.樹突狀細胞與肝癌的免疫治療.中華肝臟病雜志, 2003, 11(3):133-134.
11. Park HY, Jin JO, Song MG, et al.Expression of dendritic cell markers on cultured neutrophils and its modulation by anti-apoptotic and pro-apoptotic compounds.Exp Mol Med, 2007, 39(4):439-449.
12. Curiel TJ, Coukos G, Zou L, et al.Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.Nat Med.2004, 10(9):942-949.
13. Palucka AK, Ueno H, Fay J, et al.Dendritic cells:a critical player in cancer therapy?.J Immunother.2008, 31(9):793-805.
14. 宋海峰, 周軍, 潘科, 等.抑制SOCS1聯合OK-432刺激的DC疫苗抗腫效應的初步研究.癌癥.2008, 27(7):685-691.
15. Quah BJ, O'Neill HC.The immunogenicity of dendritic cell-derived exosomes.Blood Cells Mol Dis.2005, 35(2):94-110.
16. 莫世發, 賈乾斌.細胞免疫功能變化與肝癌的關系研究進展.中國普外基礎與臨床雜志, 2012, 19(4):456-458.
17. Tatsumi T, Takehara T, Yamaguchi S, et al.Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.Hepatology.2007, 45(1):22-30.
18. Palmer DH, Midgley RS, Mirza N, et al.A phaseⅡstudy of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma.Hepatology.2009, 49(1):124-132.
19. Shen L, Evel-Kabler K, Strube R, et al.Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity.Nat Biotechnol.2004, 22(12):1546-1553.
20. 黃啟超, 雷小英, 劉艷, 等.siRNA沉默SOCS1表達增強IFN-α2a-NGR的抗腫瘤效應.細胞與分子免疫學雜志, 2010, 26(5):412-415.
21. 于鴻, 陳陽, 張健, 等.SOCS1-siRNA沉默SOCS1基因表達對臍血樹突狀細胞生物學活性的影響.中國實驗診斷學, 2012, 16(10):1794-1796.
22. Evel-Kabler K, Song XT, Aldrich M, et al.SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling.J Clin Invest.2006, 116(1):90-100.
23. Aldrich M, Sanders D, Lapteva N, et al.SOCS1 downregulation in dendritic cells promotes memory T-cell responses.Vaccine.2008, 26(8):1128-1135.
24. Hashimoto M, Ayada T, Kinjyo I, et al.Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation.Cancer Sci.2009, 100(4):730-736.
25. Zitzmann K, Brand S, De Toni EN, et al.SOCS1 silencing enhances antitumor activity of typeⅠIFNs by regulating apoptosis in neuro-endocrine tumor cells.Cancer Res.2007, 67(10):5025-5032.
26. Kobayashi T, Yoshimura A.Keeping DCs awake by putting SOCS1 to sleep.Trends Immunol.2005, 26(4):177-179.
27. Gilboa E.Knocking the SOCS1 off dendritic cells.Nat Biotechnol.2004, 22(12):1521-1522.

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Inhibitory Effect of iAPA-DC/CTL on SMMC-7721 Xenograft in Nude Mice

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