弓形虫非复制型尿嘧啶营养缺陷型疫苗株对肿瘤的免疫治疗作用

摘要/Abstract

摘要：

【提要】刚地弓形虫（Toxoplasma gondii）是一种单细胞寄生原虫, 入侵机体后可诱导机体产生抗弓形虫免疫应答, 这种免疫应答与抗肿瘤免疫应答有相似之处。近年的研究发现, 弓形虫非复制型尿嘧啶营养缺陷型疫苗株（nonreplicating avirulent uracil auxotroph vaccine strain, cps）能有效地抑制多种实体瘤的进展。本文就弓形虫cps株对小鼠卵巢癌、胰腺癌和黑色素瘤的免疫治疗进展进行综述, 以期为个体化癌症免疫治疗提供有价值的参考。

关键词: 刚地弓形虫, 非复制型尿嘧啶营养缺陷型疫苗株, 卵巢癌, 胰腺癌, 黑色素瘤

Abstract:

Toxoplasma gondii is a single-cell parasitic protozoan, its invading can induce anti-T. gondii immune responses in the host, which resemble the anti-tumor immune response. Recent studies have demonstrated that the nonreplicating avirulent uracil auxotroph vaccine strain(cps) of T. gondii can effectively inhibit the progression of multiple solid tumors. This review focuses on the progress of immunotherapy using cps strain of T. gondii for ovarian cancer, pancreatic cancer, and melanoma in mice which may provide a valuable reference for individualized cancer immunotherapy.

Key words: Toxoplasma gondii, Nonreplicating avirulent uracil auxotroph vaccine strain, Ovarian cancer, Pancreatic cancer, Melanoma

中图分类号:

R382.5

吴一凡, 吕芳丽. 弓形虫非复制型尿嘧啶营养缺陷型疫苗株对肿瘤的免疫治疗作用[J]. 中国寄生虫学与寄生虫病杂志, 2017, 35(3): 288-293.

Yi-fan WU, Fang-li LYU. Application of nonreplicating avirulent uracil auxotroph vaccine strain of Toxoplasma gondii in tumor immunotherapy[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2017, 35(3): 288-293.

参考文献 50

[1]	Weiss LM, Dubey JP.Toxoplasmosis: a history of clinical observations[J]. Int J Parasitol, 2009, 39(8): 895-901.
[2]	吴斌, 吕芳丽. CD8+T 细胞免疫应答在刚地弓形虫感染免疫中的功能研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2014, 32(2): 143-147.
[3]	Fox BA, Bzik DJ.De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii[J]. Nature, 2002, 415(6874): 926-929.
[4]	Fox BA, Bzik DJ.Avirulent uracil auxotrophs based on disruption of orotidine-5′-monophosphate decarboxylase elicit protective immunity to Toxoplasma gondii[J]. Infect Immun, 2010, 78(9): 3744-3752.
[5]	Fox BA, Bzik DJ, Kiah LS.Non-replicating Toxoplasma gondii reverses tumor-associated immunosuppression[J]. Onco-immunology, 2013, 2(11): e26296.
[6]	Gigley JP, Fox BA, Bzik DJ.Cell-mediated immunity to Toxoplasma gondii develops primarily by local Th1 host immune responses in the absence of parasite replication[J]. J Immunol, 2009, 182(2): 1069-1078.
[7]	Behnke MS, Fentress SJ, Mashayekhi M, et al. The polymorphic pseudokinase ROP5 controls virulence in Toxoplasma gondii by regulating the active kinase ROP18[J]. PLoS Pathog, 2012, 8(11): e1002992.
[8]	Butcher BA, Fox BA, Rommereim LM, et al. Toxoplasma gondii rhoptry kinase ROP16 activates STAT3 and STAT6 resulting in cytokine inhibition and arginase-1-dependent growth control[J]. PLoS Pathog, 2011, 7(9): e1002236.
[9]	Rosowski EE, Lu D, Julien L, et al. Strain-specific activation of the NF-kappaB pathway by GRA15, a novel Toxoplasma gondii dense granule protein[J]. J Exp Med, 2011, 208(1): 195-212.
[10]	Braun L, Brenier-Pinchart MP, Yogavel M, et al. A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation[J]. J Exp Med, 2013, 210(10): 2071-2086.
[11]	Peixoto L, Chen F, Harb OS, et al. Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses[J]. Cell Host Microbe, 2010, 8(2): 208-218.
[12]	Fox BA, Sanders KL, Rommereim LM, et al. Secretion of rhoptry and dense granule effector proteins by nonreplicating Toxoplasma gondii uracil auxotrophs controls the development of antitumor immunity[J]. PLoS Genet, 2016, 12(7): e1006189.
[13]	Ravindran S, Lodoen MB, Verhelst SH, et al. 4-Bromophenacyl bromide specifically inhibits rhoptry secretion during Toxoplasma invasion[J]. PLoS One, 2009, 4(12）: e8143.
[14]	Denkers EY, Butcher BA, Del RL, et al. Neutrophils, dendritic cells and Toxoplasma[J]. Int J Parasitol, 2004, 34(3): 411-421.
[15]	Johnson LL, VanderVegt FP, Havell EA. Gamma interferon-dependent temporary resistance to acute Toxoplasma gondii infection independent of CD4+ or CD8+ lymphocytes[J]. Infect Immun, 1993, 61(12): 5174-5180.
[16]	Hunter CA, Subauste CS, Van Cleave VH, et al. Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha[J]. Infect Immun, 1994, 62(7): 2818-2824.
[17]	Hemmi H, Akira S.TLR signalling and the function of dendritic cells[J]. Chem Immunol Allergy, 2005, 86: 120-135.
[18]	Bagchi A, Herrup EA, Warren HS, et al. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists[J]. J Immunol, 2007, 178(2): 1164-1171.
[19]	曾治民, 何静, 刘安文. Toll样受体信号传导与炎症相关肿瘤的关系[J]. 中国癌症杂志, 2011, 21(6): 489-494.
[20]	Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870, 893, a novel CD40 agonist monoclonal antibody[J]. J Clin Oncol, 2007, 25(7): 876-883.
[21]	Eliopoulos AG, Davies C, Knox PG, et al. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily[J]. Mol Cell Biol, 2000, 20(15): 5503-5515.
[22]	Conejo-Garcia JR, Benencia F, Courreges MC, et al. Tumor-infiltrating dendritic cell precursors recruited by a β-defensin contribute to vasculogenesis under the influence of Vegf-A[J]. Nat Med, 2004, 10(9): 950-958.
[23]	Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival[J]. Nat med, 2004, 10(9): 942-949.
[24]	Trinchieri G.Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity[J]. Annu Rev Immunol, 1995, 13: 251-276.
[25]	Mashayekhi M, Sandau MM, Dunay IR, et al. CD8α(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites[J]. Immunity, 2011, 35(2): 249-259.
[26]	Airoldi I, Di Carlo E, Cocco C, et al. Endogenous IL-12 triggers an antiangiogenic program in melanoma cells[J]. Proc Natl Acad Sci USA, 2007, 104(10): 3996-4001.
[27]	Murugaiyan G, Saha B.Protumor vs antitumor functions of IL-17[J]. J Immunol, 2009, 183(7): 4169-4175.
[28]	Jemal A, Siegel R, Ward E, et al. Cancer statistics[J]. CA Cancer J Clin, 2008, 58(2): 71-96.
[29]	Schreiber RD, Old LJ, Smyth MJ.Cancer immunoediting: integrating immunity′s roles in cancer suppression and promotion[J]. Science, 2011, 331(6024): 1565-1570.
[30]	Huarte E, Cubillos-Ruiz JR, Nesbeth YC, et al. Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity[J]. Cancer Res, 2008, 68(18): 7684-7691.
[31]	Baird JR, Fox BA, Sanders KL, et al. Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment[J]. Cancer Res, 2013, 73(13): 3842-3851.
[32]	Scarlett UK, Cubillos-Ruiz JR, Nesbeth YC, et al. In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppres-sive to immunostimulatory cells[J]. Cancer Res, 2009, 69(18): 7329-7337.
[33]	Palucka K, Banchereau J.Cancer immunotherapy via dendritic cells[J]. Nat Rev Cancer, 2012, 12(4): 265-277.
[34]	Benson A, Murray S, Divakar P, et al. Microbial infection induced expansion of effector T cells overcomes the suppressive effects of regulatory T cells via an IL-2 deprivation mechanism[J]. J Immunol, 2012, 188(2): 800-810.
[35]	Komita H, Zhao X, Katakam AK, et al. Conditional interleukin-12 gene therapy promotes safe and effective antitumor immunity[J]. Cancer gene ther, 2009, 16(12): 883-891.
[36]	Wilson DC, Matthews S, Yap GS.IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii infection[J]. J Immunol, 2008, 180(9): 5935-5945.
[37]	Zou W, Restifo NP.T(H)17 cells in tumour immunity and immunotherapy[J]. Nat Rev Immunol, 2010, 10(4): 248-256. [38] Murphy TL, Tussiwand R, Murphy KM. Specificity through cooperation: BATF-IRF interactions control immune-regulatory networks[J]. Nat Rev Immunol, 2013, 13(7): 499-509.
[39]	Gazzinelli RT, Wysocka M, Hayashi S, et al. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii[J]. J Immunol, 1994, 153(6): 2533-2543.
[40]	Bougdour A, Durandau E, Brenier-Pinchart MP, et al. Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression[J]. Cell Host Microbe, 2013, 13(4): 489-500.
[41]	吕文超, 崔云甫. 胰腺癌流行病学和病因学研究进展[J]. 世界华人消化杂志, 2011, 19(27): 2805-2809.
[42]	Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer[J]. Cancer Cell, 2012, 21(6): 822-835.
[43]	Sideras K, Braat H, Kwekkeboom J, et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies[J]. Cancer Treat Rev, 2014, 40(4): 513-522.
[44]	Panni RZ, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages to combat cancer[J]. Immunotherapy, 2013, 5(10): 1075-1087.
[45]	Sanders KL, Fox BA, et al. Attenuated Toxoplasma gondii stimulates immunity to pancreatic cancer by manipulation of myeloid cell populations[J]. Cancer Immunol Res, 2015, 3(8): 891-901.
[46]	Pützer BM, Rödicker F, Hitt MM, et al. Improved treatment of pancreatic cancer by IL-12 and B7.1 costimulation: antitumor efficacy and immunoregulation in a nonimmunogenic tumor model[J]. Mol Ther, 2002, 5(4): 405-412.
[47]	Zaidi MR, Merlino G.The two faces of interferon-γ in cancer[J]. Clin Cancer Res, 2011, 17(19): 6118-6124.
[48]	Sanders KL, Fox BA, Bzik DJ.Attenuated Toxoplasma gondii therapy of disseminated pancreatic cancer generates long-lasting immunity to pancreatic cancer[J]. Oncoimmunology, 2016, 5(4): e1104447.
[49]	Wang J, Saffold S, Cao X, et al. Eliciting T cell immunity against poorly immunogenic tumors by immunization with dendritic cell-tumor fusion vaccines[J]. J Immunol, 1998, 161(10): 5516-5524.
[50]	Baird JR, Byrne KT, Lizotte PH, et al. Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge[J]. J Immunol, 2013, 190(1): 469-478.