新型高效Exosomes的制备及其诱导癌胚抗原特异性抗肿瘤免疫反应的研究
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摘要
癌胚抗原(Carcinoembryonic antigen,CEA)是一种高度糖基化的、分子量为180kD的癌抗原,在人类腺癌例如结肠、胰腺、乳腺、肺癌等中高度表达。在正常成人结肠上皮及其它内胚层来源的组织呈低表达。其组织的表达特性使其成为肿瘤特异性免疫治疗的一种潜在“靶点”。联合应用CEA蛋白和佐剂、CEA多肽、抗CEA独特性抗体及以CEA为基础的重组痘病毒疫苗均可诱导出CEA特异性的细胞毒T淋巴细胞(Cytotoxic Tlymphocyte,CTL)。然而,作为自身蛋白及其免疫耐受性,CEA的免疫原性比较低。因此,改善以CEA为基础的肿瘤的免疫治疗的疗效是当今免疫治疗研究的热点之一。
热疗(Hyperthermia)是目前癌症治疗特别是在某些实体瘤局部治疗中被认为即简单又有效的方法。实验表明,热处理本身就能增强肿瘤细胞的免疫原性。至少有两种机制可以阐明热处理能够提高抗肿瘤免疫的效应。其一,热处理后可以使细胞大量表达热休克蛋白70(Heat shock protein 70,HSP70),而HSP70可以将胞内肿瘤抗原处理加工直接提呈给肿瘤特异性T细胞。其二,热处理可以使肿瘤细胞的主要组织相容性复合体Ⅰ(Major histocomtability complex Ⅰ,MHC-Ⅰ)抗原表达增加。在人类黑色素瘤的Ⅲ期临床研究表明,经过热处理后,局部肿瘤得到控制,病人生存期延长。HSP是高度保守的一类蛋白,在应急情况下,例如热处理,可使其合成增加。如今,有大量的研究表明,肿瘤来源的HSP-多肽复合物可诱导抗肿瘤免疫反应。因此,热疗已成为直接活化免疫系统发挥抗肿瘤作用的方法之一。
白细胞介素18(Interleukin 18,IL-18),其前称为γ干扰素诱导因子
Carcinoembryonic antigen (CEA) is a heavily glycosylated oncofetal antigen that is overexpressed in human adenocarcinomas, especially in colon, pancreas, breast and lung, and, at a lower level, in normal adult colonic epithelium and other endodermally derived tissues. CEA represents a well-characterized oncofetal glycoprotein. The tissue expression pattern makes CEA a potential target for tumor specific immunotherapy. Recent studies have revealed that CEA-specific cytotoxic T lymphocytes (CTL) can be induced after the administration of CEA protein mixed with adjuvants, altered peptide of CEA, anti-idiotype antibodies of CEA, and CEA-based recombinant poxvirus vaccines. However, as a self-protein and due to immune tolerance, CEA is poorly immunogenic, thus more efforts should be put into exploring a successful strategy to improve the efficiency of CEA-based tumor immunotherapy.Hyperthermia is considered as a promising approach in cancer therapy, especially as a local regional treatment modality for certain solid tumors. Heat treatment per se can enhance the immunogenicity of tumor cells. Currently, it is thought that there are at least two mechanisms for enhancing anti-tumor immunity. One is high expression of HSP70, which may be associated with the processing and presentation of endogenous tumor antigens directly to tumor-specific T-cells; another
is the augmentation of MHC-I expression on the tumor cells. A randomized phase III pilot study in human melanoma has been completed showing improvement of local tumor control and survival benefits in patients with multiple lesions after hyperthermia treatment. HSP are highly conserved proteins whose synthesis is indued under stress conditions, including heat stress. The accumulating evidences have demonstrated that tumor-derived HSP-peptide complexes can elicit antitumor response. Therefore, Hyperthermia, by up-regulating HSP70 or other stress proteins (e.g HSP110 and grpl70) and by causing local necrosis in tumor tissue, has the potential to directly activate the immune response against tumors.IL-18, previously known as IFN-γ-inducing factor, is also a promising vaccine adjuvant. IL-18 has a variety of effects on immune response including stimulating NK, T and B cells to express high levels of IFN-γ, promoting IL-2 secretion of the stimulated cells and inducing T-cell proliferation, enhancing killing activity of CTL and NK cells and up-regulating dentritic cell (DC) maturation. It also exerts pro-inflammatory properties by inducing the release of IL-1B, TNF-a, chemokines, and then chemoattract DC, T cells and polymorphonuclear cells. We and others have previously identified that IL-18 has potent anti-tumor immunity, mainly mediated by cytotoxic CD4~+, CD8~+ T cells and NK cells. IL-18 anti-tumor effects also involve FasL-mediated cytotoxicity and ihibition of tumor angiogenesis. Therefore, the pleiotropic activities of IL-18 suggest that this cytokine plays an important role in innate and adaptive immune responses, especially in anti-tumor immunity.Exosomes, described as membrane vesicles with a diameter of 30-90nm, can be released into the extracellular milieu upon the fusion of small internal compartments with the plasma membrane by many types of cells, such as mast cells, T and B lymphocytes, DC, platelets and tumor cells. Recently, studies have suggested that exosomes can serve as a new kind of vaccine with promising therapeutic effects in cancer immunotherapy. Exosomes derived from DC pulsed with tumor antigen peptide elicit potent tumor-specific immune responses. Exosomes derived from tumor cells are also a source of shared tumor rejection antigens for CTL cross-priming, and
DCs loaded with tumor-derived exosomes induce tumor antigen-specific CTL in vitro and CD8~+ T-cell-dependent cross-protection against different poorly immunogenic tumors in vivo. In combination with proper adjuvants, exosomes-based cancer vaccines can enhance the host immune responses against tumors. For example, exosomes admixed with CpG oligonucleotides are efficient in prophylactic and therape
热疗(Hyperthermia)是目前癌症治疗特别是在某些实体瘤局部治疗中被认为即简单又有效的方法。实验表明,热处理本身就能增强肿瘤细胞的免疫原性。至少有两种机制可以阐明热处理能够提高抗肿瘤免疫的效应。其一,热处理后可以使细胞大量表达热休克蛋白70(Heat shock protein 70,HSP70),而HSP70可以将胞内肿瘤抗原处理加工直接提呈给肿瘤特异性T细胞。其二,热处理可以使肿瘤细胞的主要组织相容性复合体Ⅰ(Major histocomtability complex Ⅰ,MHC-Ⅰ)抗原表达增加。在人类黑色素瘤的Ⅲ期临床研究表明,经过热处理后,局部肿瘤得到控制,病人生存期延长。HSP是高度保守的一类蛋白,在应急情况下,例如热处理,可使其合成增加。如今,有大量的研究表明,肿瘤来源的HSP-多肽复合物可诱导抗肿瘤免疫反应。因此,热疗已成为直接活化免疫系统发挥抗肿瘤作用的方法之一。
白细胞介素18(Interleukin 18,IL-18),其前称为γ干扰素诱导因子
Carcinoembryonic antigen (CEA) is a heavily glycosylated oncofetal antigen that is overexpressed in human adenocarcinomas, especially in colon, pancreas, breast and lung, and, at a lower level, in normal adult colonic epithelium and other endodermally derived tissues. CEA represents a well-characterized oncofetal glycoprotein. The tissue expression pattern makes CEA a potential target for tumor specific immunotherapy. Recent studies have revealed that CEA-specific cytotoxic T lymphocytes (CTL) can be induced after the administration of CEA protein mixed with adjuvants, altered peptide of CEA, anti-idiotype antibodies of CEA, and CEA-based recombinant poxvirus vaccines. However, as a self-protein and due to immune tolerance, CEA is poorly immunogenic, thus more efforts should be put into exploring a successful strategy to improve the efficiency of CEA-based tumor immunotherapy.Hyperthermia is considered as a promising approach in cancer therapy, especially as a local regional treatment modality for certain solid tumors. Heat treatment per se can enhance the immunogenicity of tumor cells. Currently, it is thought that there are at least two mechanisms for enhancing anti-tumor immunity. One is high expression of HSP70, which may be associated with the processing and presentation of endogenous tumor antigens directly to tumor-specific T-cells; another
is the augmentation of MHC-I expression on the tumor cells. A randomized phase III pilot study in human melanoma has been completed showing improvement of local tumor control and survival benefits in patients with multiple lesions after hyperthermia treatment. HSP are highly conserved proteins whose synthesis is indued under stress conditions, including heat stress. The accumulating evidences have demonstrated that tumor-derived HSP-peptide complexes can elicit antitumor response. Therefore, Hyperthermia, by up-regulating HSP70 or other stress proteins (e.g HSP110 and grpl70) and by causing local necrosis in tumor tissue, has the potential to directly activate the immune response against tumors.IL-18, previously known as IFN-γ-inducing factor, is also a promising vaccine adjuvant. IL-18 has a variety of effects on immune response including stimulating NK, T and B cells to express high levels of IFN-γ, promoting IL-2 secretion of the stimulated cells and inducing T-cell proliferation, enhancing killing activity of CTL and NK cells and up-regulating dentritic cell (DC) maturation. It also exerts pro-inflammatory properties by inducing the release of IL-1B, TNF-a, chemokines, and then chemoattract DC, T cells and polymorphonuclear cells. We and others have previously identified that IL-18 has potent anti-tumor immunity, mainly mediated by cytotoxic CD4~+, CD8~+ T cells and NK cells. IL-18 anti-tumor effects also involve FasL-mediated cytotoxicity and ihibition of tumor angiogenesis. Therefore, the pleiotropic activities of IL-18 suggest that this cytokine plays an important role in innate and adaptive immune responses, especially in anti-tumor immunity.Exosomes, described as membrane vesicles with a diameter of 30-90nm, can be released into the extracellular milieu upon the fusion of small internal compartments with the plasma membrane by many types of cells, such as mast cells, T and B lymphocytes, DC, platelets and tumor cells. Recently, studies have suggested that exosomes can serve as a new kind of vaccine with promising therapeutic effects in cancer immunotherapy. Exosomes derived from DC pulsed with tumor antigen peptide elicit potent tumor-specific immune responses. Exosomes derived from tumor cells are also a source of shared tumor rejection antigens for CTL cross-priming, and
DCs loaded with tumor-derived exosomes induce tumor antigen-specific CTL in vitro and CD8~+ T-cell-dependent cross-protection against different poorly immunogenic tumors in vivo. In combination with proper adjuvants, exosomes-based cancer vaccines can enhance the host immune responses against tumors. For example, exosomes admixed with CpG oligonucleotides are efficient in prophylactic and therape
引文
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2. Ras E, van der Burg SH, Zegveld ST, et al. Identification of potential HLA-A 0201 restricted CTL epitopes derived from the epithelial cell adhesion molecule (Ep-CAM) and the carcinoembryonic antigen (CEA) [J]. Hum. Immunol, 1997, 53(1): 81-89.
3. Kawashima I, Tsai V, Southwood S, et al. Identification of HLA-A3-restricted cytotoxic T lymphocyte epitopes from carcinoembryonic antigen and HER-2/neu by primary in vitro immunization with peptide-pulsed dendritic cells [J]. Cancer Res, 1999, 59(2): 431-435.
4. Kim C, Matsumura M, Saijo K, et al. In vitro induction of HLA-A2402-restricted and carcinoembryonic-antigen-specific cytotoxic T lymphocytes on fixed autologous peripheral blood cells [J]. Cancer Immunol Immunother, 1998, 47(2): 90-96.
5. McAneny D, Ryan CA, Beazley RM, et al. Results of a phase I trial of a recombinant vaccinia virus that expresses carcinoembryonic antigen in patients with advanced colorectal cancer [J]. Ann Surg Oncol, 1996, 3(5): 495-500.
6. Samanci A, Yi Q, Fagerberg J, et al. Pharmacological administration of granulocyte/macrophage -colony-stimulating factor is of significant importance for the induction of a strong humoral and cellular response in patients immunized with recombinant carcinoembryonic antigen [J]. Cancer Immunol Imraunother, 1998, 47(3): 131-147.
7. Marshall JL, Hoyer RJ, Toomey MA, et al. Phase I study in cancer patients of a diversified prime and boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses [J]. J Clin Oncol, 2000, 18(23): 3964-3973.
8. von Mehren M, Arlen P, Tsang KY, et al. Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas [J]. Clin Cancer Res, 2000, 6(6): 2219-2228.
9. Tsang KY, Zhu MZ, Nieroda CA, et al. Phenotypic stability of a cytotoxic T-cell line directed against an immunodominant epitope of human carcinoembryonic antigen [J]. Clin Cancer Res, 1997, 3 (12 Pt 1): 2439-2449.
10. Zhu MZ, Marshall J, Cole D, et al. Specific cytolytic T-cell responses to human CEA from patients immunized with recombinant avipox-CEA vaccine [J]. Clin Cancer Res, 2000, 6(1): 24-33.
11. Kobayashi T. Hyperthermia for brain tumors [J]. Jpn J Hyperthermic Oncol, 1993, 79(1): 245-249.
12. Moroz P, Jones SK, Gray BN. Magnetically mediated hyperthermia: current status and future directions [J]. Int J Hyperthermia, 2002, 18(4): 267-284.
13. Van der Zee J. Heating the patient: a promising approach? [J]. Annu Oncol, 2002, 13(8): 1173-1184.
14. Kubista B, Trieb K, Blahovec H, et al. Hyperthermia increases the susceptibility of chondro- and osteosarcoma cells to natural killer cell-mediated lysis [J]. Antieaneer Res, 2002, 22(2A): 789-792.
15. Mise K, Kan N, Okino T, et al. Effect of heat treatment on tumor cells and antitumor e. ector cells [J]. Cancer Res, 1990, 50(19): 6199-6202.
16. Mondovi B, Santoro AS, Strom R, et al. Increased immunogenicity of Ehrlich ascites cells after heat treatment [J]. Cancer, 1972, 30(4): 885-888.
17. Ozdemirli M, Akdeniz H, el-Khatib M, et al. A novel cytotoxicity of CD4~+ Th1 clones on heat-shocked tumor targets. I. Implications for internal disintegration model for target death and hyperthermia treatment of cancers [J]. J Immunol, 1991, 147(11): 4027-4034
18. Wells AD, Malkovsky M. Heat shock proteins, tumor immunogenicity and antigen presentation: an integrated view [J]. Immunol Today, 2000, 21(3): 129-132.
19. Ito A, Shinkai M, Honda H, et al. Augmentation of MHC class Ⅰ antigen presentation via heat shock protein expression by hyperthermia [J]. Cancer Immunol Immunother, 2001, 50(10): 515-522.
20. Overgaard J, Gonzales D, Hulshof MCCM, et al. Randomized trials of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma [J]. Lancet, 1995, 345(8949): 540-543.
21. Tamura Y, Peng P, Liu K, et al. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations [J]. Science, 1997, 278(5335): 117-120.
22. Udono H, Srivastava PK. Heat shock protein 70-associated peptides elicit specific cancer immunity [J]. J Exp Med, 1993, 178(4): 1391-1396.
23. Parmiani G, Castelli C, Dalerba P, et al. Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going?[J]. J Natl Cancer Inst, 2002, 94(11): 805-818.
24. Gracie J, Robertson S, Mclnnes I. Interleukin-18 [J]. J Leuk Bio, 2003, 73(2): 213-219.
25. Komai-Koma M, Gracie J, Wei X, et al. Chemoattraction of human T ceils by IL-18 [J]. J Immunol, 2003, 170(2): 1084-1090.
26. Gutzmer R, Langer K, Mommert S, et al. Human dendritic cells express the IL-18R and are chemoattracted to IL-18 [J]. J Immunol, 2003, 171(12): 6363-6371.
27. Puren A, Fantuzzi G., Gu Y, et al. Interleukin-18 (IFNT-gamma-inducing factor) induces IL-8 and IL-1β via TNFa production from non-CD14~+ human blood mononuclear cells [J]. J Clin Invest, 1998, 101(3): 711-721.
28. Xia D, Zheng S, Zhang W, et al. Effective induction of therapeutic anti-tumor immunity by dendritic cells coexpressing interleukin-18 and tumor antigen [J]. J Mol Med, 2003, 81(9): 585-96.
29. Chaput N, Taieb J, Schartz NE, et al. Exosome-based immunotherapy [J]. Cancer Immunol Immunother, 2004, 53(3): 234-239.
30. Chaput N, Schartz NE, Andre F, et al. Exosomes for immunotherapy of cancer [J]. Adv Exp Med Biol, 2003, 532: 215-221.
31. Zitvogel L, Regnault A, Lozier A, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes [J]. Nat Med, 1998, 4(5): 594-600.
32. Wolfers J, Lozier A, Raposo G, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming [J]. Nat Med, 2001, 7(3): 297-303.
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