摘要
正常机体免疫系统通过免疫监视功能可发现并清除癌变的细胞,而肿瘤病人特别是晚期病人则表现为抗肿瘤免疫能力的低下。临床上通过给病人接种肿瘤疫苗或CTL细胞过继免疫的方法试图激发病人的抗肿瘤免疫能力以杀伤肿瘤,但是在实际应用中却发现肿瘤治疗效果有限。肿瘤病人免疫低下导致抗肿瘤免疫治疗不能达到理想效果,其主要原因是肿瘤细胞会持续不断地产生大量膜型和分泌型生物活性物质(tumor-derived factors,TDFs),诱导多种免疫抑制性细胞产生,并在肿瘤内聚集,形成稳定的肿瘤免疫抑制微环境,进而保护肿瘤逃避机体的免疫攻击。在肿瘤免疫逃逸研究中,有两群免疫抑制细胞即髓系来源抑制性细胞(Myeloid derived suppressor cells,MDSC)和调节性T细胞(Regulatory T cells,Treg)在其中起了主导作用,是目前肿瘤免疫研究中关注的热点。
MDSC是由粒细胞、单核/巨噬细胞和处于早期分化阶段的髓系前体细胞组成的细胞群。正常生理情况下,MDSC主要集中在骨髓,但是在肿瘤、慢性感染、创伤应急、GVHD、辐照影响下,骨髓内MDSC可大量增殖,并向各组织器官聚集。肿瘤诱导的MDSC参与肿瘤免疫逃逸的认识,最早见于上世纪80年代Yong MR研究小组的报道。他们发现恶性Lewis肺癌在小鼠骨髓中诱导出一群具有免疫抑制功能的细胞亚群。后续又有大量的文献报道头颈部肿瘤,鳞状上皮癌,乳腺癌和小细胞性肺癌等患者外周血与肿瘤浸润组织存在大量的MDSC,切除肿瘤组织后,肿瘤病人外周血MDSC细胞数目降低。肿瘤动员的MDSC从骨髓进入外周血后,在肿瘤微环境的影响下可进一步分化发育成新的细胞亚群。我们实验室前期研究中发现外周常规髓系来源抑制细胞(conventional MDSC,cMSC)进入肿瘤后进一步分化为分化为新的亚群,分化髓系来源抑制细胞(differentiated MDSC,dMSC)。这群细胞膜表面低表达CD11b和Gr1,与cMSC相比,高分泌IL-6和高表达MMP9,具有很强的促肿瘤转移功能(未发表结果)。研究发现肿瘤组织内MDSC主要通过诱导机体免疫耐受促进肿瘤生长进展,进入肿瘤后还可进一步分化为血管内皮细胞,参与肿瘤血管的生成。可见,MDSC的肿瘤内聚集与肿瘤的生长进展密切相关,那么MDSC是如何在肿瘤内聚集的?哪些因子和信号通路参与了这一过程?对此我们还缺乏充分的认识。
1980年Berendt等最先报道了肿瘤组织内存在一群具有抑制功能的T细胞亚群,但限于当时技术条件的限制,未能进一步找到这类T细胞的特异性标志物。直到1995年,日本学者Sakaguchi等找到了抑制性T细胞的膜表面标志CD4~+CD25~+,才提出调节性T细胞(regualtory T cells,Treg)概念,后续研究发现Treg特异表达转录因子Foxp3。临床已经证实多种癌症患者(如胰腺癌、胃肠道的恶性肿瘤、早期非小细胞肺癌和晚期的卵巢癌等)外周血和肿瘤病灶内有Treg细胞数量增多或比例增加现象。与MDSC类似,切除肿瘤后外周和肿瘤内Treg恢复到正常水平,而肿瘤复发时Treg水平又升高。小鼠纤维肉瘤肿瘤模型研究发现,Treg选择性的在肿瘤内聚集,进展性晚期肿瘤内浸润淋巴细胞主要为Treg细胞,肿瘤内注射抗CD4抗体清除CD4~+T细胞,可显著增强抗肿瘤免疫应答,肿瘤病灶明显消退,该结果提示肿瘤诱导的Treg主要在肿瘤内发挥抑制效应。那么肿瘤内Treg是如何产生的?哪些信号通路参与了这一过程?目前还不是非常明确。
死亡受体Fas,其主要功能为介导细胞凋亡,但其也可介导活化、增殖和炎症信号。我们实验室和其他研究室的研究证明,Fas活化后的DC可大量分泌炎性细胞因子和趋化因子,介导炎症反应。越来越多的证据表明慢性炎症与肿瘤免疫耐受的形成密切相关。那么肿瘤内的Fas信号是否也可介导炎症反应,影响机体的免疫功能呢?我们通过小鼠3LL肺癌为模型,研究了肿瘤内Fas信号对肿瘤生长以及机体免疫功能的影响,并对其相关机制进行了探讨。
首先,我们检测了3LL小鼠肺癌细胞Fas的表达,RT-PCR和Western blot分析发现3LL细胞表达Fas。Fas活化型抗体Jo2(5μg/ml)刺激3LL细胞,发现3LL细胞对Jo2诱导凋亡抵抗。为体外研究Fas信号对3LL细胞生长增殖的影响,我们用Jo2和anti-mFasL中和性抗体处理3LL细胞,MTT法观察了3LL细胞的生长,发现Jo2和anti-mFasL对3LL细胞的体外增殖没有明显影响。为进一步观察体内肿瘤Fas信号对肿瘤生长的影响,我们复制了过表达Fas的肺癌模型。我们将编码Fas基因全长的Fas-WT和Fas基因胞内段缺失的Fas-DN真核表达质粒转染3LL肺癌细胞,通过G418加压筛选,有限稀释,流式细胞筛选的方法获得了稳定表达这两个基因的细胞株3LL/Fas-WT、3LL/Fas-DN。体外MTT法检测这两株细胞和3LL细胞生长增殖,发现与3LL细胞相比3LL/Fas-WT、3LL/Fas-DN生长增殖没有明显差异。随后我们将3LL/Fas-WT、3LL、3LL/Fas-DN这三株细胞接种到C57BL/6J小鼠皮下,观察了肿瘤生长和小鼠的生存情况。结果发现与3LL/Fas-DN,3LL两株细胞相比,过表达Fas的3LL/Fas-WT肿瘤生长迅速,相应的接种3LL/Fas-WT的荷瘤小鼠生存期显著降低。该结果表明,Fas信号可促进肺癌细胞的体内增殖、进展。那么,Fas信号介导肿瘤生长进展是否依赖于Fas配体FasL的活化呢?为此,我们又将三株肺癌细胞接种到FasL功能缺失的Tnfsf6gld(gld)小鼠,结果发现3LL/Fas-WT的生长优势消失,三组肿瘤生长大小和生存期差异不明显。该结果显示,Fas信号促进肺癌细胞3LL生长的作用需依赖于FasL。
Fas信号体内可促进肿瘤的生长进展,而体外Jo2刺激3LL细胞,细胞生长增殖没有明显改变。那么Fas信号对肿瘤的促进作用是否是通过调节机体免疫功能而实现的呢?我们分析了3LL/Fas-WT、3LL、3LL/Fas-DN三株细胞接种C57BL/6J成瘤后第7天,第14天,肿瘤组织内免疫抑制细胞MDSC、Treg的浸润情况。免疫组织化学结果发现,接种肺癌细胞后第7天,肿瘤组织内可见Gr1~+MDSC浸润,三组肿瘤中3LL/Fas-WT肿瘤组织内MDSC的浸润最为显著,但是未见Foxp3~+Treg的浸润。到第14天,肿瘤组织内出现大量MDSC的聚集,并可见Foxp3~+Treg,三组肿瘤中3LL/Fas-WT接种肿瘤内MDSC和Treg浸润最为显著。为验证上述结果我们进一步的用Percoll密度梯度离心法分离了接种14天后肿瘤内浸润淋巴细胞(Tumor infiltrating lymphocytes,TIL),FACS分析了肿瘤内CD11b~(low)Gr1~(low)dMSC以及CD4~+Foxp3~+Treg分布,结果发现三组肿瘤组织中,3LL/Fas-WT接种的肿瘤组织内dMSC在TIL中的比例以及Foxp3~+Treg占CD4~+T细胞中的比例最高。IHC和FACS的结果表明,3LL细胞过表达Fas可促进免疫抑制细胞MDSC和Treg在肿瘤内的聚集。在Fas信号介导的MDSC和Treg的肿瘤内聚集过程中,我们发现MDSC先于Treg出现,那么MDSC是否介导了随后Treg在肿瘤内的浸润呢?我们接种1x10~63LL/Fas-WT细胞于小鼠皮下,小鼠腹腔内注射anti-Gr1+抗体(RB6-8C5)清除MDSC,肿瘤内浸润的Treg显著降低),该结果提示MDSC参与诱导了肿瘤内Treg的形成。
Fas介导的信号对MDSC,Treg肿瘤内聚集有促进作用,已知Fas信号介导了多种炎性细胞的趋化,那么Fas信号促MDSC,Treg肿瘤内聚集效应,是否是通过增强肿瘤细胞对MDSC,Treg的趋化迁移而实现的呢?于是我们体外Jo2刺激3LL细胞,趋化小失迁移实验观察了Jo2处理后上清对MDSC,Treg的趋化迁移的影响,结果显示Jo2刺激的3LL上清可明显促进MDSC的趋化,但是对Treg没有影响。已有文献报道MCP-1、VEGF在肿瘤趋化MDSC向肿瘤内聚集中起重要作用,于是我们用ELISA方法检测Jo2刺激后3LL上清中MCP-1、VEGF的表达变化,但是Jo2刺激后3LL上清中未发现这些细胞因子表达的改变。我们知道在肿瘤发生进展过程中,炎性因子和免疫抑制因子也参与诱导肿瘤免疫耐受微环境的形成。于是我们又检测了免疫耐受相关的重要炎性和免疫抑制因子IL-1β、PGE2、IL-10、TGF-β等细胞因子的表达,结果发现,Jo2刺激可明显促进3LL表达PGE2。进一步的Western blot法检测PGE2诱导生成相关代谢酶COX2的表达发现,Jo2刺激同样上调COX2的表达。有文献报道PGE2可促进DC、内皮细胞的迁移,于是我们进一步研究了PGE2在Fas促肺癌细胞趋化MDSC效应中的作用,发现COX2选择性抑制剂SC58125可显著抑制Jo2对3LL趋化MDSC迁移的增强效应。PGE2可直接作为趋化因子,也可通过上调趋化因子受体,活化细胞迁移相关信号帮助细胞的趋化迁移。那么PGE2究竟是通过什么方式参与趋化MDSC?我们发现,直接用PGE2(1μM)无法有效趋化MDSC,而将PGE2加入3LL细胞培养上清可促进趋化MDSC,该结果提示PGE2可能主要通过协同的方式促进MDSC的趋化迁移。RT-PCR检测介导PGE2细胞迁移的相关EP2、EP4受体表达,发现EP2/EP4在MDSC中高表达,同时3LL细胞中也可见表达。
在Fas信号介导的细胞增殖、组织再生、炎症反应中,Fas信号激活伴有下游MAPK,NF-ΚB的活化。于是我们检测了Jo2刺激3LL细胞后这些信号通路的活化情况。Western blot结果发现,Jo2刺激可磷酸化ERK、p38、促进NF-ΚBp65,Stat3的核转位。为进一步研究这些信号通路活化与PGE2生成的关系,我们用这些信号分子特异性的抑制剂阻断这些分子介导的信号通路,发现p38选择性抑制剂SB203580可有效阻断Jo2诱导的PGE2,提示p38信号通路的激活介导了Jo2诱导的PGE2产生。
综上所述,在本课题研究中我们首次报道了肺癌细胞3LL内Fas信号可激活下游MAPK,NF-κB下游信号通路,通过p38通路依赖的方式诱导促进3LL肺癌细胞释放PGE2,进而诱导MDSC、Treg肿瘤组织内聚集,从而促进肺癌生长的新机制。该研究结果为肿瘤免疫逃逸研究提供新的机制,同时为阻断PGE2/COX2的肿瘤免疫治疗提供了新的理论依据。
Host immune system can surveillance and kill the mutated cells,however,cancer patients,especially the advanced cancer patients,usually exhibit the impaired immunity against cancer.In order to initiate the anti-tumor immune response,several approches for the cancer immunotherapy such as injecting tumor vaccine and adoptive transfer of CTL have been used in clinic trials,however the therapeutic effect of current immunotherapy of cancer is far from that we expected.The poor curative effect may result from immunosuppressive status of cancer patients. Acummulated evidences demonstrate that tumor can consistently release tumor-derived factors(TDFs),which promote the generation of immunosuppressive cells,constituting immunosuppressive environment,thus inhibiting the host immunity against cancer.During this process,the roles of myeloid-derived suppressor cells (MDSC)and regulatory T cells(Treg)in the tumor immune esacpe attach more attraction,because of their essential role for establishing the immunosuppressive tumor microenvironment,inducing tumor escape from host immune defence.
MDSC represent a heterogeneous population comprising different myeloid cells at the early-stage of differentiation,including granulocytes,monocytes and a pool of immature cell of myelomonocytic lineage that retain the ability to form colonies on agar.Majority of MDSC inhabit in the bone marrow,and markedly increase during the vaccination,inflammation,transplantation,radiation and tumor progression.They play important roles in the immune tolerance and also in many physiological and pathological process as described above.Once immune response is trigged,MDSC mobilized form bone marrow and accumulate in the lymph organs and tissues where they exert as immune suppressor cells.The tumor associated MDSC were described for the first time in the bone marrow of Lewis lung cancer-bearing mice,and the counterpart of MDSC in human are mostly CD34+,which reported by Pak et al in patients with head and neck cancer.Subsequently,human MDSC have been characterized in the peripheral blood of patients with squamous cell carcinoma, non-small cell lung cancer and breast cancer.After the removal of tumor,MDSC in cancer patient decreased.In tumor-bearing mice,conventional MDSC(cMSC)could further differentiate into a novel subset of MDSC under the tumor microenvironment, which was named by us as the differentiated MDSC(dMSC)with the phenotype of CD11b~(low)Gr1~(low).dMSC highly express MMP-9 and produce IL-6,showing strong potential to promotie tumor metastasis(our unpublished data).Other than promoting tumor metastasis and protecting the tumor from immune attack,tumor MDSC also participate in the tumor angiogenesis by directly differentiating into vascular endothelial cells.Thus,MDSC accumulation in tumor tissue promotes tumor progression,however,which factor(s)is responsible for the MDSC migration and accumulation in tumor tissue remain unclear.
In 1980,Berendt et al reported that they found a group of T cells in tumor tissue exerting inhibitory effect on tumor immunity.Due to the limitation of bio-techniques, the features of these cells have not been well identified.Until to 1995,these T suppressor cells were characterized by Sakguchi et al as CD4~(+)CD25~(high)cells,the so-called regulatory T cells(Treg)now.And in search of specific Treg cell markers, transcription factor Foxp3 was identified to be uniquely expressed in Treg cells.In patients with cancer including pancreatic cancer,gastric enterologic cancer,non-small cell lung cancer and ovary cancer,increased Tregs were found in tumor tissue and peripheral blood.Consistent with the change of MDSC,Treg recover to normal level after removing tumor,but rebound when tumor recumce.In a murine fibrosarcoma model,selective accumulation of Treg cells in tumor tissue was studied,where the majority of tumor-infiltrating lymphocytes(TIL)in late-stage progressive tumor were Tregs.Furthermore,local depletion of CD4~(+)T cells in tumor led to eradication of well-established tumors and development of long term anti-tumor memory.This study suggested Tregs-mediated immune suppression occurs predominantly at tumor site, local reversaling Treg cells in tumor tissue,even the late stage tumor,can effectly inhibit tumor growth.Increased Treg cells in tumor was a characteristic feature in most tumors,but little is know about the mechanism which is responsible for the elevated Tregs in tumor?
Fas belongs to the TNFR super-family,which can recognize and transmit death signal.However,other than transmiting death singal,Fas also mediates inflammatory signal.We and other research group have proved Fas-ligated DC can release amounts of pro-inflammatory cytokines and chemokines,promoting inflammation.In tumors, Fas is widely expressed,and various tumor show diverse response to Fas stimulation. Some cancer cells are sensitive to Fas-mediated apoposis,but majority of them show apoptosis resistance and even grow fast upon Fas ligation.Upon to now,previous reports on Fas-induced tumor growth focused on the direct promoting effect of Fas such as tumor proliferation,motility and invasion.While the influence of Fas signal in modulating host immunity was ignored.The aim of current work is to study the role of Fas signal in lung cancer growth and its influence on the tumor immunity.
Firstly,we demonstrated that 3LL Lewis lung cancer cells constitutively expressed certain level of Fas.Upon stimulation of agonistic anti-Fas antibody Jo2, even at high concentration up to 5μg/ml,3LL cells show resistant to Fas-induced apoptosis.In vitro stimulating 3LL cells with Jo2 did not affect the 3LL growth,as detected by MTT methods.In order to investigate the effect of Fas signal on lung cancer growth in vivo,we transfected the wild type Fas(Fas-WT)vector or dominant negative Fas(Fas-DN)which lacking endocellular domain of Fas into 3LL cells,and selected stable 3LL transfectant clones highly expressing Fas-WT(3LL/Fas-WT)or Fas-DN(3LL/Fas-DN)with the pressure of G418.Prior to the in vivo experiments, we tested whether overexpression of Fas on 3LL cells affected the growth rates of these cells in vitro.In vitro growth rates of the Fas-transfectants and parental cells were compared by MTT method.No difference in in vitro growth rate was observed between parental 3LL cells and 3LL Fas-transfectants,demonstrating that the basal proliferation rate of the 3LL cells was not altered by Fas-overexpression.In contrast, when 3LL/Fas-WT cells,3LL/Fas-DN cells or parental 3LL cells,were subcutaneously inoculated into C57BL6/J mice,we observed the accelerated growth of 3LL/Fas-WT and reduced growth of 3LL/Fas-DN compared with parental 3LL cells respectively.Accordingly,the survival percentage of 3LL/Fas-WT-bearing mice cells reduced more significantly than that of mice bearing parental 3LL cells or 3LL/Fas-DN cells.In order to confirm the specific role of Fas signal on promoting in vivo 3LL lung cancer cells growth,we subcutaneously inoculated 3LL/Fas-WT cells, 3LL/Fas-DN cells or parental 3LL cells,into FasL-deficient gld mice,and found there was no significant difference in the tumor growth and mice survive among these groups.Collectively,we can conclude that Fas over-expression in lung cancer cells promotes lung cancer growth in vivo,and which is dependent on the Fas/FasL interaction.
Next,we wanted to know what's the mechanisms for the promotion of lung cancer growth in vivo by Fas signal in lung cancer cells.Because accumulation of MDSC and Treg in tumor is involved in the tumor immune escape and tumor progression,we analyzed the accumulation of MDSC and Treg in the tumor tissues 7 days and 14 days after inoculation with 3LL/Fas-WT,3LL/Fas-DN,or parental 3LL into C57BL/6J mice.In C57BL/6J mice model,MDSC appeared to infiltrate tumor 7 days later,and increased 14 days after cancer cell inoculation.Among three groups,more markedly infiltration of MDSC was observed in tumors formed by 3LL/Fas-WT than that tumors formed by parental 3LL cells and 3LL/Fas-DN cells at either 7~(th)day or 14~(th) day.No obvious infiltration of Foxp3~(+)Treg cells was observed in three groups of tumors 7 days later,but appeared at 14~(th)day.Among threee groups of tumors the most significant infiltration of Foxp3~(+)Treg cells was observed in 3LL/Fas-WT transplanted tumor.
Further,we analyzed the percentages of dMSC(a MDSC subset identified in our previous work)and Treg cells in the tumor-infiltrating cells isolated by Percoll gradient centrifugation.We found the more infiltration of dMSC in tumor with Fas-overexpression lung cancer cells.Together with above data,these results demonstrate that Fas signal in lung cancer cells can recruit more MDSC and Foxp3~(+) Treg cells into tumor tissues.
Considering that MDSC can induce generation of Treg cells and the Treg accumulation in the Fas-overexpressing tumor was later than MDSC accumulation as observed above,we wondered whether the rapid accumulation of MDSC could induce subsequent accumulation of Treg cells in the Fas-overexpressing tumor.Through in vivo depleting Gr-1+ cells in mice beating 3LL/Fas-WT,we found the ratio of tumor-infiltrating Treg cells decreased significantly,thus confirming our hypothesis.
As more accumulation of MDSC and Treg cells was observed in Fas-overexpressing lung cancer,we examined whether Fas-ligated 3LL lung cancer cells can chemoattract more MDSC or Treg cells in vitro.We found that supematant of Fas-ligated 3LL cells was more effective in chemoattracting Gr1~(+)CD11b~(+)MDSC than control supernatant derived from isotype-treated 3LL lung cancer cells.However, no significant chemoattraction of CD4~(+)Foxp3~(+)Treg cells was observed.So,Fas ligation can promote 3LL lung cancer cells to chemoattract more MDSC but not Treg cells.
Then,we went further to look for which factor(s)derived from Fas-ligated lung cancer cells was responsible for the enhanced chemoattraction of MDSC.As reported, Fas signaling is associated with inflammation by increasing chemokines secretion and chemoattracting inflammatory cells,and VEGF,MCP-1 have been shown to be crucial for MDSC migration.Therefore,we detected the expression of VEGF,MCP-1 in the supernatant of 3LL lung cancer cells stimulated by Jo2,however,no significant secretion of MCP-1 and VEGF was observed.Also,pro-inflammatory mediators produced by cancer cells can recruit and activate inflammatory cells,which further stimulate tumor progression.Thus,we also detected the pro-inflammatory cytokines in the supernatant of Jo2-stimulated 3LL cells,and found that Fas ligation could significantly induce 3LL cells to secrete PGE2.Accordingly,Fas ligation also significantly increased COX2 expression in 3LL lung cancer cells.It was known that COX-2-derived PGE2 can promote migration of cells including tumor cells,DC, endothelial cells.We wondered whether the increased production of PGE2 by Fas-ligated cancer cells was responsible for the increased chemoattraction of MDSC? When COX2 selective inhibitor SC-58125 was used to pre-treat the Fas-ligated 3LL cancer cells,the chemoattracting effect of Fas-ligated 3LL cancer cells on MDSC was abrogated.These data suggest that Fas signal can induce lung cancer cells to secrete more PGE2 which contributes to the enhanced chemoattraction of MDSC.RT-PCR results showed the expression of PGE2 receptors EP2,EP4 in MDSC,supporting the conclusion that PGE2-mediated chemoattraction for MDSC.
Finally,we wanted to know which pathway(s)responsible for the increased PGE2 production in Fas-ligated lung cancer cells.Activation of MAPK and NF-κB pathways has been shown to contribute to the Fas-mediated pro-inflammatory factor production and to be associated with tumor growth and invasion.Jo2 stimulation can activate the ERK,p38,NF-κB pathways in 3LL lung cancer cells,stat3 signaling activation in tumor is essential for downregulation of the host immunity.Then we also detected the Star3 signaling pathway upon Fas ligation,and found Jo2 stimulation promoted the nuclear tranlocation of Stat3,indicating Stat3 activation may also be involved in the Fas-mediated lung cancer immune escape.To elucidate which pathway(s)was essential for the increased production of PGE2 by Fas ligation, specific inhibitors for signaling pathways were used to pretreat 3LL lung cancer cells before Jo2 stimulation.We found p38 MAPK specific inhibitor SB203580 could markedly suppress the Jo2-induced PGE2 production,indicating Fas-activated p38 MAPK signaling pathway is responsible for the increased PGE2 production by Fas-ligated lung cancer cells.
In summary,we demonstrate that Fas signal can activate the MEK,p38 MAPK and NF-ΚB signaling pathway in lung cancer cells,and p38 MAPK mediates the Fas ligation-induced PGE2 production,which contribute to Fas-induced MDSC and Tregs accumulation in tumor and subsequently promote lung cancer growth in vivo.Our study elucidates the novel immune regulatory role of Fas signal in tumor immune escape,providing new mechanistic explanation for blockade of COX2 in the treatment of tumor growth.
引文
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