肿瘤相关抗原P1A的诱导表达及其增强细胞毒T细胞杀伤恶性肿瘤的研究
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摘要
当前,恶性肿瘤(包括恶性血液系统疾病)的发生率和死亡率正处于不断上升之中。尽管包括异基因干细胞移植等先进的医疗技术和治疗手段大大改善了恶性血液系统疾病患者的预后,但晚期和多次治疗后复发的患者预后仍然很差。因此探索新的治疗方法,已成为改善此类患者预后的迫切需要。
恶性肿瘤的免疫治疗早已成为人们关注的焦点之一。在过去的十年中,免疫治疗在多种肿瘤治疗中都获得了令人注目的成就,这些治疗手段包括细胞因子治疗,局部免疫刺激,肿瘤疫苗和异基因干细胞移植后的全身淋巴细胞输注(DLI)等。然而,这些治疗方法获得部分成功的同时,却未能使大多数肿瘤患者实现真正意义的治愈,甚至连肿瘤部分控制或缩小的目标也未达到。其原因是肿瘤细胞的免疫逃避,或者是机体免疫细胞的无能。进一步的研究表明,这种令人失望的现象是因为肿瘤细胞缺乏有效的免疫源性从而导致机体的免疫细胞无法识别或抗原呈递细胞无法有效地递呈抗原。因此,如何增强肿瘤组织／细胞的抗原性,是肿瘤免疫研究领域一个殛待解决的首要问题。
癌／睾丸抗原(Cancer/testis antigens CTAs)是一类在胚胎组织和滋养层细胞优势表达的抗原,并在大约40%的恶性肿瘤患者中存在,而在正常组织中几乎没有表达。表观遗传学研究表明,该类基因在肿瘤中的表达大多数情况下处于低水平或沉默状态,其原因是其该类基因启动子的异常甲基化造成的。由于睾丸等组织的免疫豁免特性和CTA抗原的分布特点,使得该类抗原成为近年来免疫治疗的重要靶点之一。我们的前期研究表明,P1A是一种重要鼠类CT抗原,在多种肿瘤细胞有异常分布。该基因的表达受甲基化调控,5-杂氮胞苷等药物处理可恢复其表达。鉴于上述背景,我们从下述几个方面进行研究,旨在增强肿瘤细胞的免疫源性,并通过有效的抗原呈递,进而有效刺激机体产生有效的抗肿瘤作用。
一、用5-杂氮胞苷处理多种肿瘤细胞,并在5-杂氮胞苷处理前后对所处理肿瘤细胞进行P1A的DNA和mRNA检测,进而阐明5-杂氮胞苷对肿瘤细胞P1A表达的影响,筛选受甲基化调控、便于体外、体内免疫研究的肿瘤细胞株(本研究中T细胞淋巴瘤细胞系EL-4符合上述条件)。
二、对P1A的抗原表位(多肽片段)进行人工合成,以此多肽片段刺激经细胞因子诱导成熟的树突状细胞(dendritic cells, DCs),而后以一定数量经多肽刺激的DCs多次免疫BALB／c小鼠,使之产生针对P1A多肽的特异性细胞毒T细胞(Cytotoxic T cell, CTL).
三、以免疫磁珠法分离小鼠脾脏内的CTL(CD90+T细胞),以流式细胞仪检测P1A特异性CTL对肿瘤细胞的体外杀伤效果；同时分离CD4+和CD8+,进一步探讨其各自在免疫杀伤中的作用。
四、构建荷瘤动物模型,在一定的时机经尾静脉给予荷瘤小鼠注射经特异免疫刺激产生的细胞毒T细胞,并以生理盐水、无关肽刺激的细胞毒T细胞为对照,观察P1A特异性CTL对肿瘤组织生长的抑制作用。
五、以CFSE为示踪剂,进一步检测了特异性CTL在荷瘤小鼠体内的归巢运动及分布,进一步探讨克服免疫逃逸的有效方法。
六、通过对不同方法处理的肿瘤细胞进行流式检测,探讨CTL杀伤肿瘤细胞机制。
结果发现,5-杂氮胞苷诱导癌／睾丸抗原P1A的表达存在明显的量效和时效关系。通过DC细胞的递呈,有效地刺激小鼠产生P1A特异性细胞毒T细胞,体外、体内均证实其对P1A恢复表达的肿瘤细胞或组织均有杀伤作用；我们同时还发现CD4+T细胞在特异性杀伤中起重要的作用,这种杀伤与癌／睾丸抗原的表达和识别密切相关。此外,我们对P1A特异性CTL杀伤的机制进行了初步探讨。
Background:Nowadays, much progress has been made in the treatment of hematological malignancies. However, a significant number of patients develop disease recurrence even after hematopoietic stem cell transplantation (HSCT). It is urgent to develop novel strategies to promote remission and prolong the survival of these patient populations by using alone or in combination with standard therapy. Cancer/testis antigens (CTAs) are ideal candidates for cancer immunotherapy because of their restricted expression profile in normal tissues. However, so far the outcome of immunotherapy targeting CTAs has been rather disappointed in clinical setting because CTAs are down-regulated by CpG methylation in their promoter regions. Methods:We re-induced mouse CTA P1A by treatment of demethylation agent 5-aza-2-deoxycytidine (5-aza-dCyd) and generated P1A-specific cytotoxic lymphocytes (CTLs) by immunizing BALB/C mouse with dendritic cell pulsed with P1A-specific peptide, established a tumor-bearing animal model in BALB/C mouse, observed the killing activities of P1A-specific CTL in vitro and in vivo. Results:We found that the demethylation of P1A promoter facilitated the proper homing of P1A-specific CTLs and its recognition of the target cells. Moreover, P1A specific CTLs had specific cytotoxic effect against target cells both in vitro and in vivo. Finally, we showed that similar to CD8+CTLs, CD4+T lymphocytes played a crucial role in eradicating tumor cells. Conclusion:Taken together, our results suggest that the induced CTA is a potential target for adoptive immunotherapy of cancer.
恶性肿瘤的免疫治疗早已成为人们关注的焦点之一。在过去的十年中,免疫治疗在多种肿瘤治疗中都获得了令人注目的成就,这些治疗手段包括细胞因子治疗,局部免疫刺激,肿瘤疫苗和异基因干细胞移植后的全身淋巴细胞输注(DLI)等。然而,这些治疗方法获得部分成功的同时,却未能使大多数肿瘤患者实现真正意义的治愈,甚至连肿瘤部分控制或缩小的目标也未达到。其原因是肿瘤细胞的免疫逃避,或者是机体免疫细胞的无能。进一步的研究表明,这种令人失望的现象是因为肿瘤细胞缺乏有效的免疫源性从而导致机体的免疫细胞无法识别或抗原呈递细胞无法有效地递呈抗原。因此,如何增强肿瘤组织／细胞的抗原性,是肿瘤免疫研究领域一个殛待解决的首要问题。
癌／睾丸抗原(Cancer/testis antigens CTAs)是一类在胚胎组织和滋养层细胞优势表达的抗原,并在大约40%的恶性肿瘤患者中存在,而在正常组织中几乎没有表达。表观遗传学研究表明,该类基因在肿瘤中的表达大多数情况下处于低水平或沉默状态,其原因是其该类基因启动子的异常甲基化造成的。由于睾丸等组织的免疫豁免特性和CTA抗原的分布特点,使得该类抗原成为近年来免疫治疗的重要靶点之一。我们的前期研究表明,P1A是一种重要鼠类CT抗原,在多种肿瘤细胞有异常分布。该基因的表达受甲基化调控,5-杂氮胞苷等药物处理可恢复其表达。鉴于上述背景,我们从下述几个方面进行研究,旨在增强肿瘤细胞的免疫源性,并通过有效的抗原呈递,进而有效刺激机体产生有效的抗肿瘤作用。
一、用5-杂氮胞苷处理多种肿瘤细胞,并在5-杂氮胞苷处理前后对所处理肿瘤细胞进行P1A的DNA和mRNA检测,进而阐明5-杂氮胞苷对肿瘤细胞P1A表达的影响,筛选受甲基化调控、便于体外、体内免疫研究的肿瘤细胞株(本研究中T细胞淋巴瘤细胞系EL-4符合上述条件)。
二、对P1A的抗原表位(多肽片段)进行人工合成,以此多肽片段刺激经细胞因子诱导成熟的树突状细胞(dendritic cells, DCs),而后以一定数量经多肽刺激的DCs多次免疫BALB／c小鼠,使之产生针对P1A多肽的特异性细胞毒T细胞(Cytotoxic T cell, CTL).
三、以免疫磁珠法分离小鼠脾脏内的CTL(CD90+T细胞),以流式细胞仪检测P1A特异性CTL对肿瘤细胞的体外杀伤效果；同时分离CD4+和CD8+,进一步探讨其各自在免疫杀伤中的作用。
四、构建荷瘤动物模型,在一定的时机经尾静脉给予荷瘤小鼠注射经特异免疫刺激产生的细胞毒T细胞,并以生理盐水、无关肽刺激的细胞毒T细胞为对照,观察P1A特异性CTL对肿瘤组织生长的抑制作用。
五、以CFSE为示踪剂,进一步检测了特异性CTL在荷瘤小鼠体内的归巢运动及分布,进一步探讨克服免疫逃逸的有效方法。
六、通过对不同方法处理的肿瘤细胞进行流式检测,探讨CTL杀伤肿瘤细胞机制。
结果发现,5-杂氮胞苷诱导癌／睾丸抗原P1A的表达存在明显的量效和时效关系。通过DC细胞的递呈,有效地刺激小鼠产生P1A特异性细胞毒T细胞,体外、体内均证实其对P1A恢复表达的肿瘤细胞或组织均有杀伤作用；我们同时还发现CD4+T细胞在特异性杀伤中起重要的作用,这种杀伤与癌／睾丸抗原的表达和识别密切相关。此外,我们对P1A特异性CTL杀伤的机制进行了初步探讨。
Background:Nowadays, much progress has been made in the treatment of hematological malignancies. However, a significant number of patients develop disease recurrence even after hematopoietic stem cell transplantation (HSCT). It is urgent to develop novel strategies to promote remission and prolong the survival of these patient populations by using alone or in combination with standard therapy. Cancer/testis antigens (CTAs) are ideal candidates for cancer immunotherapy because of their restricted expression profile in normal tissues. However, so far the outcome of immunotherapy targeting CTAs has been rather disappointed in clinical setting because CTAs are down-regulated by CpG methylation in their promoter regions. Methods:We re-induced mouse CTA P1A by treatment of demethylation agent 5-aza-2-deoxycytidine (5-aza-dCyd) and generated P1A-specific cytotoxic lymphocytes (CTLs) by immunizing BALB/C mouse with dendritic cell pulsed with P1A-specific peptide, established a tumor-bearing animal model in BALB/C mouse, observed the killing activities of P1A-specific CTL in vitro and in vivo. Results:We found that the demethylation of P1A promoter facilitated the proper homing of P1A-specific CTLs and its recognition of the target cells. Moreover, P1A specific CTLs had specific cytotoxic effect against target cells both in vitro and in vivo. Finally, we showed that similar to CD8+CTLs, CD4+T lymphocytes played a crucial role in eradicating tumor cells. Conclusion:Taken together, our results suggest that the induced CTA is a potential target for adoptive immunotherapy of cancer.
引文
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[1]Winter H, van den Engel NK, Riittinger D, et al. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines. J Transl Med,2007; 5:56
[2]Wieder T, Braumuller H, Kneilling M, et al. T cell-mediated help against tumors. Cell Cycle,2008; 7:2974-7
[3]Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol,1986; 136:2348-2357
[4]Zhu J, Paul WE. CD4 T cells:fates, functions, and faults. Blood,2008; 112:1557-1569
[5]Gorelik L, Fields PE, Flavell RA. Cutting edge:TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol,2000; 165:4773-4777
[6]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol,2005; 6:1123-1132
[7]O'Garra A, Murphy KM. O'Garra A, et al. From IL-10 to IL-12:how pathogens and their products stimulate APCs to induce T(H)1 development.Nat Immunol,2009; 10:929-32
[8]徐媛媛,李惠民.骨髓增殖性疾病JAK2 V617F研究进展.中国实验血液 学杂志,2009；17：238-242
[9]Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol,2007; 7:179-190
[10]Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol,2002; 2:933-944
[11]Zhu J, Jankovic D, Grinberg A, Guo L, Paul WE.Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc Natl Acad Sci U S A,2006; 103:18214-9
[12]Jankovic D, Kullberg MC, Noben-Trauth N, et al. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile. J Immunol, 2000; 164:3047-3055
[13]Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature,2006; 441:231-234
[14]Das J, Ren G, Zhang L, et al. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med,2009; 206:2407-16
[15]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med,2003; 198:1875-1886
[16]Darrah PA, Patel DT, De Luca PM, et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med, 2007; 13:843-850
[17]Romagnani S.Thl and Th2 in human diseases.Clin Immunol Immunopathol, 1996; 80:225-35
[18]Weaver CT, Harrington LE, Mangan PR, et al. Th17:an effector CD4 T cell lineage with regulatory T cell ties. Immunity,2006; 24:677-688
[19]Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol, 2004; 22:531-562
[20]Greenberg PD, Kern DE, Cheever MA. Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2-T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med,1985; 161:1122-1134
[21]Perez-Diez A, Joncker NT, Choi K, et al. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood,2007 June 15; 109:5346-5354
[22]Bevan MJ. Helping the CD8(+) T-cell response. Nat Rev Immunol,2004; 4:595-602
[23]DeNardo DG, Barreto JB, Andreu P, et al. CD4 (+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell,2009; 16:91-102
[24]Hu HM, Winter H, Urba WJ, et al. Divergent Roles for CD4+ T Cells in the Priming and Effector/Memory Phases of Adoptive Immunotherapy. The Journal of Immunology,2000; 165:4246-4253
[25]Antony PA, Piccirillo CA, Akpinarli A, et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol,2005;174:2591-2601
[26]Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood,2008; 112:362-373
[27]Lin WW, Karin M A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest,2007; 117:1175-1183
[28]Langowski JL, Kastelein RA, Oft M. Swords into plowshares:IL-23 repurposes tumor immune surveillance. Trends Immunol.2007; 28:207-212
[29]Nam JS, Terabe M, Kang MJ, et al. Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res,2008; 68:3915-3923
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[31]Kaiga T, Sato M, Kaneda H, et al. Systemic Administration of IL-23 Induces Potent Antitumor Immunity Primarily Mediated through Thl-Type Response in Association with the Endogenously Expressed IL-12. J Immunol,2007;178:7571-80
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[35]Yu L, Liu C, Vandeusen J, et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet,2005; 37:265-274
[36]Bai XF, Liu JQ, Joshi PS, et al. Different lineages of P1A-expressing cancer cells use divergent modes of immune evasion for T-cell adoptive therapy. Cancer Res,2006; 66:8241-8249
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[1]Winter H, van den Engel NK, Riittinger D, et al. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines. J Transl Med,2007; 5:56
[2]Wieder T, Braumuller H, Kneilling M, et al. T cell-mediated help against tumors. Cell Cycle,2008; 7:2974-7
[3]Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol,1986; 136:2348-2357
[4]Zhu J, Paul WE. CD4 T cells:fates, functions, and faults. Blood,2008; 112:1557-1569
[5]Gorelik L, Fields PE, Flavell RA. Cutting edge:TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol,2000; 165:4773-4777
[6]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol,2005; 6:1123-1132
[7]O'Garra A, Murphy KM. O'Garra A, et al. From IL-10 to IL-12:how pathogens and their products stimulate APCs to induce T(H)1 development.Nat Immunol,2009; 10:929-32
[8]徐媛媛,李惠民.骨髓增殖性疾病JAK2 V617F研究进展.中国实验血液 学杂志,2009；17：238-242
[9]Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol,2007; 7:179-190
[10]Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol,2002; 2:933-944
[11]Zhu J, Jankovic D, Grinberg A, Guo L, Paul WE.Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc Natl Acad Sci U S A,2006; 103:18214-9
[12]Jankovic D, Kullberg MC, Noben-Trauth N, et al. Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4+ lymphocytes with a Th2 cytokine profile. J Immunol, 2000; 164:3047-3055
[13]Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature,2006; 441:231-234
[14]Das J, Ren G, Zhang L, et al. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med,2009; 206:2407-16
[15]Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med,2003; 198:1875-1886
[16]Darrah PA, Patel DT, De Luca PM, et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med, 2007; 13:843-850
[17]Romagnani S.Thl and Th2 in human diseases.Clin Immunol Immunopathol, 1996; 80:225-35
[18]Weaver CT, Harrington LE, Mangan PR, et al. Th17:an effector CD4 T cell lineage with regulatory T cell ties. Immunity,2006; 24:677-688
[19]Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol, 2004; 22:531-562
[20]Greenberg PD, Kern DE, Cheever MA. Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2-T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med,1985; 161:1122-1134
[21]Perez-Diez A, Joncker NT, Choi K, et al. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood,2007 June 15; 109:5346-5354
[22]Bevan MJ. Helping the CD8(+) T-cell response. Nat Rev Immunol,2004; 4:595-602
[23]DeNardo DG, Barreto JB, Andreu P, et al. CD4 (+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell,2009; 16:91-102
[24]Hu HM, Winter H, Urba WJ, et al. Divergent Roles for CD4+ T Cells in the Priming and Effector/Memory Phases of Adoptive Immunotherapy. The Journal of Immunology,2000; 165:4246-4253
[25]Antony PA, Piccirillo CA, Akpinarli A, et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol,2005;174:2591-2601
[26]Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood,2008; 112:362-373
[27]Lin WW, Karin M A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest,2007; 117:1175-1183
[28]Langowski JL, Kastelein RA, Oft M. Swords into plowshares:IL-23 repurposes tumor immune surveillance. Trends Immunol.2007; 28:207-212
[29]Nam JS, Terabe M, Kang MJ, et al. Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res,2008; 68:3915-3923
[30]Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood,2003; 101:2620-262
[31]Kaiga T, Sato M, Kaneda H, et al. Systemic Administration of IL-23 Induces Potent Antitumor Immunity Primarily Mediated through Thl-Type Response in Association with the Endogenously Expressed IL-12. J Immunol,2007;178:7571-80
[32]Muranski P, Restifo NP. Adoptive immunotherapy of cancer using CD4+T cells. Curr Opin Immunol,2009; 21:200-208
[33]Kamiryo Y, Eto M, Yamada H, et al. Donor CD4 T cells are critical in allogeneic stem cell transplantation against murine solid tumor.Cancer Res, 2009; 69:5151-5158
[34]Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med,2008; 358:2698-2703
[35]Yu L, Liu C, Vandeusen J, et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet,2005; 37:265-274
[36]Bai XF, Liu JQ, Joshi PS, et al. Different lineages of P1A-expressing cancer cells use divergent modes of immune evasion for T-cell adoptive therapy. Cancer Res,2006; 66:8241-8249