摘要
自然杀伤细胞(Natural killer cell, NK细胞)作为固有免疫系统的重要成员在机体抗肿瘤免疫中扮演重要的角色。使用NK细胞进行抗肿瘤治疗已引起人们高度的重视,目前已有研究进入了临床实验阶段。基于NK细胞的肿瘤免疫治疗包括内源性NK细胞的诱导活化、同种反应性NK细胞输注、体外扩增的自体或供者NK细胞及NK细胞系的过继转输等。相比较而言,自体或同种异体NK细胞在进行抗瘤治疗时存在一定的局限性,而永生化的人NK细胞系因具有较强的细胞毒作用、体外易扩增培养、且不存在其他细胞污染等优点,可以克服自体或异体NK细胞的局限性,具有很好的临床应用前景。现有可用于肿瘤治疗的NK细胞系(NK-92细胞)由西方国家建立,尽管HLA分子不匹配是NK细胞行驶功能的有益因素,但是由于不同种族间HLA分子的差异很可能在受者体内产生抗HLA的抗体从而抑制免疫治疗的效果,故西方国家建立的NK细胞系可能不适合用于中国肿瘤病人的治疗。因此,建立国人的NK细胞系并将其用于肿瘤治疗尤为重要。
另外,肿瘤的诊断及分期对于临床治疗方案的制定至关重要。肺癌作为恶性肿瘤中最常见的死亡原因,严重威胁人类的健康。肺癌的高转移率和复发率严重阻碍肺癌患者生存期的提高,寻找用于循环肿瘤细胞监测的标志物并建立合适的检测方法成为亟需解决的问题。
本研究利用流式细胞术对本室已建立的人NK细胞系(NKG细胞)的表型、活化状态及功能分子的表达进行分析；利用3H掺入实验测定不同剂量辐照后NKG细胞的增殖情况；利用51Cr杀伤实验测定NKG细胞的细胞毒活性；建立人卵巢癌裸鼠腹水瘤模型评价NKG细胞的体内抗肿瘤活性；利用波浪式生物反应器建立NKG细胞大规模培养的工艺流程,建立NKG细胞主细胞库和工作细胞库,并按《药典》三部(2005年版)的相关要求进行了细胞鉴别试验、无菌试验、外源性因子检测、致瘤性检查及急性毒性试验。另外,应用实时荧光定量PCR的方法检测LunX等多种肿瘤标志物mRNA的水平,分析LunX mRNA与肺癌病理分期及临床治疗效果之间的关系。利用上述方法所取得的研究结果如下：
1.NKG细胞表型及功能分子的表达
NKG细胞是本研究室863课题组于2003年建立的永生化的人NK细胞株。NKG细胞悬浮生长,成团细胞较多,倍增时间为2-3天。NKG细胞的表型鉴定为CD56+CD 16-CD27- CD3-αβTCR-γδTCR- CD4- CD8- CD 19- CD 161- CD45+。NKG细胞表面表达高水平CD2、CD58、CD11a、CD54、CD11b及CD11c等粘附分子；高表达共刺激分子CD48。NKG细胞表面表达抑制性受体CD94/NKG2A、CD158b和CD85j,同时亦表达高水平NKp30、NKp44、NKp46、NKG2D和NKG2C等活化性受体。另外,与细胞杀伤功能相关的TRAIL、FasL、granzyme B、perforin和IFN-γ等均在NKG细胞中表达。上述结果表明,NKG细胞具有活化性NK细胞的特征。
2.NKG细胞的抗肿瘤细胞毒活性及其分子机制
NKG细胞对多种肿瘤细胞系均有较强的杀伤活性,尤其是对SGC7901和Ho-8910细胞的杀伤活性>80%(E／T=20／1)。NKG细胞对Ho-8910细胞的杀伤活性明显高于NK-92、NKL及YT细胞。体外抗体阻断及中和实验表明NKG细胞的细胞毒活性主要依赖于NKG2D和NKp30识别机制。当γ辐照剂量达800cGy时,辐照后的NKG细胞失去增殖能力,但在48小时内维持其对肿瘤细胞的杀伤活性。体外实验进一步证明800cGy辐照后的NKG细胞对原代分离的人卵巢癌细胞具有较强的杀伤活性(75%-45%,E／T=20／1)。
3.人卵巢癌小鼠模型中NKG细胞的免疫治疗作用
利用Ho-8910细胞以腹腔注射的方式接种裸鼠,成功建立人卵巢癌裸鼠腹水瘤模型。当将800cGy辐照后的NKG细胞与Ho-8910细胞按5：1混合后接种裸鼠,结果显示小鼠成瘤时间由28～44天延迟至90～135天,成瘤率由100%明显降低至50%。NKG细胞治疗组小鼠腹围明显减少,尽管在观察时间内50%小鼠死亡,但其平均生存时间由61.5天明显延长至210.2天。以上结果表明NKG细胞在小鼠体内对人卵巢癌细胞具有明显的杀伤功能。
当在Ho-8910细胞接种后第21天,给予800cGy辐照后的NKG细胞进行治疗,结果表明治疗组小鼠成瘤时间由28～38天延后至56～66天,小鼠成瘤率由100%降低至62.5%,成瘤鼠病情进展较缓慢,平均生存时间由64.6天延长至119.6天。当在Ho-8910细胞接种后第35天选择已成瘤小鼠,给予800cGy辐照后的NKG细胞进行治疗,结果表明治疗后小鼠腹围变化较对照组明显减慢,尽管最终治疗组小鼠亦全部死亡,但其平均生存时间由64.2天明显延长至93.6天。上述动物模型的结果表明,辐照后NKG细胞具有明显的治疗卵巢癌的作用。
4.NKG细胞大规模培养工艺的建立
利用波浪式生物反应器建立NKG细胞大规模连续培养的工艺流程,具体流程如下：接种密度：2.0×104cells／ml；培养基：a-MEM完全培养基(a-MEM液体培养基含10%新生牛血清、10%马血清),添加终浓度为100U／ml的rhIL-2；接种体积：500ml,分别于接种后2、4、6天补加500ml完全培养基及rhIL-2溶液(终浓度为100U／ml)；最大培养体积：<2000ml。培养条件：37℃,5.0%C02,C02流速为0.15L／min,7rpm／7。。按照该工艺流程培养得到的NKG细胞数量、纯度及杀伤活性等均可满足临床治疗的要求。
5.NKG细胞急性毒性检测
使用高于临床使用剂量150倍的NKG细胞(1×108cells／鼠),经800cGy辐照后通过腹腔注射的方式输入C57BL／6小鼠体内,连续观察7天,三批小鼠均为未发生毒性反应、过敏反应、局部刺激反应；实验组及对照组小鼠体重增加平稳,小鼠体重及体重增加量两组之间均无显著性差异,说明NKG细胞无急性毒性作用。
6.NKG细胞种子库的建立及检定
利用本研究建立的NKG细胞大规模培养工艺,建立主细胞库及工作细胞库。对工作细胞库的检定结果表明,NKG细胞的表型与原始库一致,无细菌、真菌及支原体污染,外源性病毒因子检测为阴性,体内外均无致瘤性。
7. LunX mRNA在非小细胞肺癌转移早期诊断及疗效评价中的作用
利用实时荧光定量RT-PCR方法检测肺癌患者、健康人、肺炎患者及其他肿瘤患者(包括乳腺癌和食道癌)的外周血或胸水样品中LunX、CEA、CK19、VEGF-c、hRNP A2/B1等肿瘤标志物nRNA的水平,结果表明LunX mRNA仅在非小细胞肺癌患者的外周血(75.0%,33／44)及胸水(92.9%,13／14)中有表达,而在健康人、肺炎、其他上皮来源的肿瘤患者外周血及结核性胸膜炎胸水中均无表达,明显优于其他各种标志物,而且外周血中LunX mRNA的水平及其阳性率与肺癌的临床分期成正相关。进一步对非小细胞肺癌患者治疗前后外周血中上述基因mRNA的表达情况进行检测分析,结果表明治疗后患者外周血中LunX、CK19 mRNA水平较治疗前明显降低,治疗前后VEGF-C、CEA、hnRNP A2/B1 mRNA表达水平无明显差异。LunX与CK19 mRNA均可作为疗效评价的指标,但因CK19mRNA在其他肿瘤患者外周血中亦有表达,故LunX mRNA作为肺痛患者治疗效果评价的指标更为灵敏和特异。
结论：
NKG细胞具有活化的人NK细胞特征,对多种肿瘤细胞具有很强的细胞毒作用。利用人卵巢癌裸鼠腹水瘤模型证明NKG细胞具有明显的抗肿瘤效应,特别是对晚期肿瘤亦具有明显的治疗效果。NKG细胞的应用将可能成为一种新的肿瘤免疫治疗方法。在此基础上,建立了体外大规模扩增NKG细胞的工艺流程,并建立了合格的主细胞库和工作细胞库,为NKG细胞用于临床的肿瘤治疗奠定了基础。此外,本研究证实检测外周血及胸水中LunX mRNA表达水平将在非小细胞肺癌转移早期诊断及治疗效果评价中具有重要作用。
Natural killer (NK) cells as part of the innate immune system are important players in the first line of defense against malignancies. The use of NK cells in immunotherapy of human cancers has been proposed and more recently trailed in a clinical context. NK cell-based cellular immunotherapy includes activation of endogenous NK cells, alloreactive NK cells, adoptive transfer of ex vivo expanded autologous NK cells or donor-derived NK cells, and adoptive transfer of NK cell line. By comparison, there are some limitations as to the efficacy of the reinfusion of ex vivo expanded autologous or allogeneic NK cells. Clinical use of human permanent NK cell lines would overcome some of the limitations, which are more cytotoxic and can be easily expanded and maintained in vitro without contamination by other lymphocytes. Until now, NK-92 is the only NK cell line that has entered clinical trials and proved to be safe and has generated anti-tumor effects. However, it was proposed that the NK cell line established in Western countries such as NK-92 might not be suitable for Chinese patients. Missing expression of donor KIR ligand(s) (HLA) in the recipient induces the function of NK cells, which would be a possible beneficial effector for the NK cell line immunotherapy; but the significant differences in HLA molecules among the races might induce HLA-antibodies in the recipient to inhibit the immune effects. So, it is important to use a NK cell line established in China for Chinese cancer patients.
In addition, tumor diagnosis and staging is critical to the clinical decision-making for tumor therapy. Lung cancer as one of the leading causes of cancer death has increasingly been an urgent problem in the world, with high frequency of tumor metastases and recurrence. Development of sensitive and specific detection methods for circulating cancer cells in peripheral blood may have important implications.
In this study, flow cytometry analysis was used to determine the phenotypical and functional characteristics of a new huaman NK cell line NKG cells. [3H] thymidine riboside incorporation was used for proliferation assay of irradiated NKG cells. Cytotoxicity assay (4 h 51Cr release) was used to detect the anti-tumor activity of NKG cells. Immunotherapy of human ovarian cancer with irradiated NKG cells was determined in xenograft mouse model. By the WAVE Bioreactor, the large-scale NKG cell culture procedure was established, and then master cell bank and working cell bank were established. The cell identification test, sterility test, exogenous factor detection, tumorigenicity and acute toxicity test were done according to (partⅢ,2005 version). Additionally, quantitative real-time RT-PCR was used to evaluate the molecular markers including LunX mRNA et al. for their specificity for lung cancer clinically. Our major findings are shown as followed:
1. Phenotypical and functional characteristics of NKG cell
NKG cell is a permanent NK cell line established by the 863 research group of Tian's lab in 2003. NKG cells as suspension cells grew with cell aggregator forming potential, and expanded for one generation in 2-3 days. The NKG cells were phenotypically identified as CD56+CD16-CD27-CD3-αβTCR-γδTCR-CD4-CD8-CD19-CD161-CD45+, and with high levels of adhesive molecules (CD2, CD58, CD11a, CD54, CD11b, CD11c) and co-stimulatory receptor CD48, an array of activating receptors (NKp30, NKp44, NKp46, NKG2D, NKG2C) and cytolysis-related receptors and molecules (TRAIL, FasL, granzyme B, perforin, IFN-y), although inhibitory receptors including CD94/NKG2A, CD158b and CD85j were detected. NKG cells displayed characteristics of activated NK cells.
2. The anti-tumor activity and its molecular mechanisms of NKG cell
NKG cells showed high cytotoxicity to several kinds of tumor cells. In particular, the cytotoxicity against the Ho-8910 and SGC7901 cells was more than 80% at the E/T ratio of 20/1. Compared with NK-92, NKL and YT cells, NKG cells were the most cytotoxic against Ho-8910 cells. High cytotoxicity of NKG cells was absolutely dependent on the recognition of NKG2D and NKp30. Irradiated at the dose up to 8 Gy, NKG cells were still with high cytotoxicity against tumor cells in 48 h, but not with proliferation. Further, the irradiated-NKG cells were demonstrated with strong cytotoxicity (75%-45%, E/T=20/1) against human primary ovarian cancer cells in vitro.
3. Immunotherapy of human ovarian cancer with irradiated NKG cells in xenograft mouse model
Ho-8910 cells were injected i.p into the nude mice to establish human ovarian tumor model. When the irradiated NKG cells were adoptively transferred into the mice together with Ho-8910 cells with ratio of 5/1, the tumorgenesis (%) was significantly decreased from 100%to 50%, and the palpable tumor developed time was delayed from 28～44 days to 90～135 days, the abdomen circumference (AC) was significantly decreased. Although 50% mice with NKG cell treatment were dead with tumor progress, the mean survival time was obviously prolonged from 61.5 to 210.2 days. These results demonstrated that the irradiated NKG cells owned the high cytotoxicity against the ovarian tumor cells in vivo.
After the mice were challenged with Ho-8910 cells for 21 days, NKG cell treatment could significantly inhibit the tumorgenesis (from 100% to 62.5%) with the delayed time of palpable tumor development (from 28～38 days to 56～66 days). The severity of ovarian cancer was attenuated as indicated by the significantly decreased AC. The mean survival time was obviously prolonged from 64.6 to119.6 days. Further, after 35 days of Ho-8910 cell challenge, the mice with palpable tumor were selected for NKG cell treatment, which could also attenuate the severity of ovarian cancer, shown by the decreased AC in the early stage of treatment and obviously prolonged mean survival time (from 64.2 to 93.6 days) although all the mice were dead with tumor progress ultimately. These results demonstrate the immunotherapy of human ovarian cancer with irradiated NKG cells.
4. Establishment of the large-scale NKG cell culture procedure
By the WAVE Bioreactor, the large-scale NKG cell culture procedure was established. Inoculation density:2.0×104cells/ml; culture medium:a-MEM complete medium (a-MEM medium contain 10% new-born calf serum and 10% horse serum) with100U/ml rhIL-2; Inoculation volume:500ml, and 500ml complete medium containing rhIL-2 (final concentration 100U/ml) were added at 2,4 and 6 days of cell inoculation respectively. Max culture volume was less than 2000ml. Culture condition was 37℃,5.0% CO2 with flow rate of 0.15L/min,7rpm/7°. The number, purity and activity of the NKG cells cultured by this procedure well meet the clinical requirements.
5. Acute toxicity test of NKG cell
The C57BL/6 mice were i.p. injected 800cGy irradiated NKG cells at a dose of 150 fold of clinical application (1x108cells/mouse). No toxic reaction, allergic reaction and local stimulation reaction was observed in successive 7 days after NKG cell transfer. There is no significance difference in the body weight between the NKG cell transferred group and control group. NKG cells were demonstrated with no acute toxicity.
6. NKG cell banks:the establishment and identification
The master cell bank and working cell bank were established by the large-scale NKG cell culture procedure. The biological assay of the working cell bank indicated that the NKG cell phenotype is identical to the primary seed cells, and with no bacterial, fungus and mycoplasma contamination, no exogenous virokine and no tumorigenicity in vitro and in vivo.
7. Diagnostic utility of LunX mRNA in early micrometastasis and therapeutic assessment for patients with primary non-small cell lung cancer
Quantitative real-time RT-PCR was used to determine LunX, CK19, CEA, VEGF-C and hnRNP A2/B1 mRNA levels in peripheral blood and pleural fluid from NSCLC patients, compared with those from patients with other epithelial cancer (esophagus cancer and breast cancer), benign lung disease (pneumonia and tuberculo pleurisy) and from healthy volunteers. In peripheral blood LunX mRNA was detectable in 75.0%(33/44) of patients with NSCLC, but not in patients with other epithelial cancer, benign lung disease or in healthy volunteers. In contrast, all other genetic markers were detected in patients with either NSCLC, other epithelia cancer or benign lung disease, and in healthy volunteers. Furthermore, LunX mRNA was detected in 92.9%(13/14) of malignant pleural fluid samples and was the only marker whose expression level was significantly different between malignant and benign pleural fluid. The expression level and positive rate of LunX mRNA in peripheral blood correlated with the pathologic stage of NSCLC. Additionally, expression of LunX mRNA and CK19 mRNA in the peripheral blood of NSCLC patients decreased shortly after clinical treatment. As for the expression of CK19 mRNA in the peripheral blood from the other epithelia cancer patients, LunX mRNA is the most specific gene marker for lung cancer and has potential diagnostic utility when measured in the peripheral blood and pleural fluid of NSCLC patients.
Conclusion:
With the characteristics of activated NK cells, NKG cells were highly cytotoxic against a series of tumor cell lines. Immunotherapy of human ovarian cancer with irradiated NKG cells was firstly demonstrated in xenograft mouse model, even for the ovarian tumor in the advance stage. Use of the NKG cell line would represent a novel immunotherapy for the treatment of human cancer in clinic. The master cell bank and working cell bank were established by the established large-scale NKG cell culture procedure, which was the base for its clinical use. Additionally, it was demonstrated that LunX mRNA is the most specific gene marker for lung cancer and has potential diagnostic utility in early micrometastasis and therapeutic assessment when measured in the peripheral blood and pleural fluid of NSCLC patients.
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