胃癌患者术后早期多种免疫活性细胞联合过继转移治疗研究
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摘要
研究背景:胃癌是我国最常见的消化道恶性肿瘤,尽管手术、化疗、新辅助化疗、放疗等治疗方法不断发展,但进展期胃癌患者预后仍然欠佳,因此迫切需要开展胃癌综合治疗新策略研究。近年来生物技术的迅猛发展为此奠定了基础。目前已知过继性细胞免疫治疗(adoptive cellular immunotherapy,ACI)对免疫原性较强的实体肿瘤如黑色素瘤和肾癌等治疗效果良好,但其对胃癌等弱免疫原性肿瘤疗效尚不明确。
根据肿瘤免疫编辑学说,胃癌患者机体预存免疫状态与肿瘤发病、进展、治疗及预后均密切相关。因此建立胃癌患者免疫状态检测技术平台并评估其预存免疫状态,从而将免疫指标加入胃癌疗效评价体系,对确定其术后免疫治疗方案及预后评价均有着重要的参考价值。
胃癌术后早期患者创伤反应刚过,机体免疫功能受到创伤进一步打击,且身体虚弱,伤口有待愈合,尚不适合进行全身化疗。而此时体内肿瘤负荷则减到最低,应该是进行免疫细胞过继转移的最佳时机。术后早期将在体外培养的多种免疫活性细胞如自体肿瘤抗原致敏的树突状细胞(DC)、细胞因子诱导的杀伤细胞(CIK)和肿瘤特异性细胞毒T淋巴细胞(CTL)回输体内,可能拮抗体内免疫抑制因素,调动并提高机体抗肿瘤免疫功能,从而取得更为满意的疗效。因此,术后早期开展多种免疫活性细胞联合过继转移治疗具有重要意义。
研究目的:建立免疫状态检测技术平台以检测胃癌患者预存免疫状态并作为疗效评价指标,构建胃癌患者手术联合免疫活性细胞过继转移治疗数据库及疗效评价体系,观察术后早期多种免疫活性细胞联合过继转移治疗对患者预后的影响,为制定新的胃癌综合治疗方案奠定基础。
研究方法: 1.建立流式细胞术检测包括外周血树突状细胞(DC)、调节性T细胞(Treg)、记忆性T细胞、自然杀伤细胞(NK)、自然杀伤T细胞(NKT)、辅助性T淋巴细胞(Th1/Th2)、细胞毒性T淋巴细胞(Tc1/Tc2)以及代表免疫细胞功能的细胞内细胞因子(IFN-γ及IL-4)在内的胃癌患者免疫状态检测技术平台;2.检测25例解放军总医院普通外科2008年10月21日至2008年12月5日新入院术前胃癌患者及25例正常健康献血者外周血样本,对胃癌患者预存免疫状态进行初步研究;3.建立胃癌患者综合治疗数据库及疗效评价平台,并对综合治疗后胃癌患者随访,开展术后早期多种免疫活性细胞联合过继转移治疗回顾性研究。
研究结果:1.胃癌患者预存免疫状态检测结果示:胃癌患者外周血调节性T细胞较正常对照组显著增多;胃癌患者外周血Th1及Tc1亚群较正常对照组明显减少,并出现Th1/Th2及Tc1/Tc2漂移呈Th2及Tc2优势现象;胃癌患者外周血记忆性T细胞CD4~+T_(CM)、CD4~+T_(EM)、CD8~+T_(CM)亚群均较正常对照组明显升高,但是在外周主要承担杀伤性效应的CD8~+T_(EM)亚群不但不升高,反而较正常人群略有下降;胃癌患者外周血DC1、DC2及DC1/DC2较正常对照组无明显改变;胃癌患者外周血NK及NKT细胞较正常对照组无明显改变;2.共有效随访68例综合治疗后胃癌患者,COX比例风险模型多因素分析显示:患者年龄、手术类型、临床分期及术后ACI治疗为影响胃癌患者预后的独立因素(P<0.05)。单因素Kaplan-Meier模型分析及Log-Rank检验结果显示患者年龄、手术类型、临床分期及术后早期ACI治疗(手术后14天内)是影响胃癌患者术后预后的相关因素(P<0.05),而患者性别、病理类型、术后化疗、术后ACI治疗次数对患者预后没有显著性影响(P>0.05)。
研究结论:1.流式细胞术检测胃癌患者免疫状态技术平台方法稳定,临床应用性良好;2.胃癌患者预存免疫状态较正常人明显低下,评估患者预存免疫状态并将免疫指标加入胃癌疗效评价体系对确定其治疗方案及疗效评价有着重要意义；3.患者年龄、手术类型、临床分期及术后ACI治疗为影响胃癌患者预后的独立因素,较晚的发病年龄(>50岁)、施行根治性手术、较早的临床分期及术后早期ACI治疗(手术后14天内)可延长术后胃癌患者生存期,而患者性别、病理类型、术后化疗、术后ACI治疗次数对患者预后没有显著性影响。本项研究表明,术后早期免疫活性细胞过继转移治疗可延长胃癌患者手术后生存期,为提高胃癌患者综合治疗水平开创了新的前景。
Background: Gastric cancer is the most common malignant tumor of digestive tract in China. Despite of the development of various treatments such as surgery, chemotherapy, neoadjuvant chemotherapy and radiotherapy, the prognosis of gastric cancer patients at advanced stage still remains poor. The possibility of applying immunotherapy for gastric cancer would therefore be highly desirable. Adoptive cellular immunotherapy (ACI) have therapeutic activity in with high immunogenic tumor such as melanoma and kidney cancer, however, it's still unclear in gastric cancer.
According to tumor immunoediting hypothesis, pre-existing immunity of gastric cancer patients is closely related to onset and progress of tumor and the poor prognosis. Therefore, establishing methods to assess pre-existing immunity and adding immunological parameters into the prognostic evaluation system of gastric cancer are significant to evaluate postoperative therapeutic strategy and efficacy.
The immunological function of early postoperative patients is decreased significantly, and it is not suitable for applying systemic chemotherapy at this point. However, the tumor load in vivo is reduced to minimum. Therefore, it is suggested that early postoperative infusion of multiple immunologicly competent cells, such as DC, CIK and CTL, should improve immune function of patients and achieve more satisfactory results.
Objective: This study was designed to establish methods for assessing pre-existing immunity of gastric cancer patients, establish database and prognostic evaluation system of gastric cancer patients after comprehensive treatment, and observe effect of early postoperative ACI on prognosis of gastric cancer patients.
Methods: 1. The flow cytometric immune function assessing system was established, including detection of peripheral DC, Treg, memory T cells, NK, NKT, Th1/Th2, Tc1/Tc2 cells and intracellular cytokine (IFN-γand IL-4) by four-color flow cytometry; 2. Preliminary analysis of pre-existing immunity of preoperative gastric cancer patients (n=25) and healthy controls (n=25) was performed by detecting subsets of DC1 (Lin~-DR~+CDl11c~+CD123~-), DC2 (Lin~-DR~+CD11c~-CD123~+), NK (CD3~-CD56~+), NKT (CD3~+ CD56~+), Treg (CD4~+CD25~+FOXP3~+), CD4~+T_(CM) (CD4~+CD45RO~+CCR7~+CD45RA~-), CD4~+T_(EM) (CD4~+CD45RO~+CCR7~-CD45RA~-), CD8~+T_(CM) (CD8~+CD45RO~+CCR7~+CD45RA~-), CD8~+T_(EM) (CD8~+CD45RO~+CCR7~-CD45RA~-), Th1 (CD4~+IFN-γ~+), Th2 (CD4~+IL-4~+), Tc1 (CD8~+IFN-γ~+) and Tc2 (CD8~+IL-4~+) cells in peripheral blood; 3. A retrospective database of 93 gastric cancer patients following surgical treatment combined with chemotherapy and/or immunotherapy from December 2004 to March 2008 was constructed firstly. Data were censored at time of death, loss to follow-up or January 1st, 2009. Survival was estimated using the Kaplan-Meier method. The factors affecting the survival time were evaluated by Cox proportional hazard model and Log-Rank test.
Results: 1. The results of preoperative gastric cancer patients show: the CD4~+CD25~+FOXP3~+ Treg of gastric cancer patients were significantly higher than the normal control group (1.993±0.830% Vs 1.229±0.656%, P <0.01); the ratios of Th1/PBL, Tc1/PBL, Th1/Th2 and Tc1/Tc2 in gastric cancer patients were significantly lower than the normal control group (3.047±1.710 % Vs 6.242±4.078 % , 6.393±5.235 % Vs 14.171±8.984 %, 1.215±0.219 % Vs 2.552±2.343 %, 1.306±0.289 % Vs 17.200±25.930 %, P<0.05); the CD4~+T_(CM), CD4~+T_(EM), CD8~+T_(cm) of gastric cancer patients were significantly higher than the normal control group (4.585±2.502% Vs 2.765±1.942%, 18.682±7.374% Vs 13.032±4.059 %, 0.455±0.472% Vs 0.127±0.165%, P <0.05), but there was no significant difference of CD8~+T_(EM) between them (8.379±3.431% Vs 8.733±3.048%, P> 0.05); there was no significant difference of DC1, DC2 and DC1/DC2 in peripheral blood between gastric cancer patients and normal control (0.201±0.095% Vs 0.198±0.087%, 0.081±0.032% Vs 0.093±0.046%, 2.693±1.636% Vs 2.561±1.486%, P> 0.05); there was no significant difference of NK and NKT in peripheral blood between gastric cancer patients and normal control (19.209±14.116% Vs 20.306±8.844%, 8.481±5.378% Vs 6.156±3.934%, P> 0.05). 2. Complete follow-up data were obtained from 68 cases of patients, majority of who were advanced stage ones. In total, 35 patients died, giving median survival time of 21 months. The estimated 3-year overall survival was 36%. In univariate analysis, age, clinical stage, type of surgery and early postoperative adoptive immunotherapy (less than 14 days after operation) were significant prognostic factors related to overall survival time (P <0.05). Gender, histopathologically diffuse type, adjuvant chemotherapy and numbers of immunotherapy were found to have no effect on survival (P> 0.05). In multivariate analysis, age, radical surgery, clinical stage, early postoperative adoptive immunotherapy (less than 14 days after operation) were found to be the statistically significant prognostic factors related to survival (P <0.05).
Conclusion: 1. The flow cytometric immune function assay was a stable method for assessing pre-existing immunity of gastric cancer patients; 2. The pre-existing immunity was poor in preoperative gastric cancer patients, which might be related to the onset and progress of tumor and the poor prognosis. Immunological parameters might be useful predictors to evaluate prognosis of gastric cancer patients; 3. The factors including age, clinical stage, radical surgery and early postoperative adoptive immunotherapy had significant effect on survival of postoperative gastric cancer patients. Early postoperative adoptive immunotherapy couid be a beneficial adjuvant therapy to improve clinical outcomes of gastric cancer patients.
根据肿瘤免疫编辑学说,胃癌患者机体预存免疫状态与肿瘤发病、进展、治疗及预后均密切相关。因此建立胃癌患者免疫状态检测技术平台并评估其预存免疫状态,从而将免疫指标加入胃癌疗效评价体系,对确定其术后免疫治疗方案及预后评价均有着重要的参考价值。
胃癌术后早期患者创伤反应刚过,机体免疫功能受到创伤进一步打击,且身体虚弱,伤口有待愈合,尚不适合进行全身化疗。而此时体内肿瘤负荷则减到最低,应该是进行免疫细胞过继转移的最佳时机。术后早期将在体外培养的多种免疫活性细胞如自体肿瘤抗原致敏的树突状细胞(DC)、细胞因子诱导的杀伤细胞(CIK)和肿瘤特异性细胞毒T淋巴细胞(CTL)回输体内,可能拮抗体内免疫抑制因素,调动并提高机体抗肿瘤免疫功能,从而取得更为满意的疗效。因此,术后早期开展多种免疫活性细胞联合过继转移治疗具有重要意义。
研究目的:建立免疫状态检测技术平台以检测胃癌患者预存免疫状态并作为疗效评价指标,构建胃癌患者手术联合免疫活性细胞过继转移治疗数据库及疗效评价体系,观察术后早期多种免疫活性细胞联合过继转移治疗对患者预后的影响,为制定新的胃癌综合治疗方案奠定基础。
研究方法: 1.建立流式细胞术检测包括外周血树突状细胞(DC)、调节性T细胞(Treg)、记忆性T细胞、自然杀伤细胞(NK)、自然杀伤T细胞(NKT)、辅助性T淋巴细胞(Th1/Th2)、细胞毒性T淋巴细胞(Tc1/Tc2)以及代表免疫细胞功能的细胞内细胞因子(IFN-γ及IL-4)在内的胃癌患者免疫状态检测技术平台;2.检测25例解放军总医院普通外科2008年10月21日至2008年12月5日新入院术前胃癌患者及25例正常健康献血者外周血样本,对胃癌患者预存免疫状态进行初步研究;3.建立胃癌患者综合治疗数据库及疗效评价平台,并对综合治疗后胃癌患者随访,开展术后早期多种免疫活性细胞联合过继转移治疗回顾性研究。
研究结果:1.胃癌患者预存免疫状态检测结果示:胃癌患者外周血调节性T细胞较正常对照组显著增多;胃癌患者外周血Th1及Tc1亚群较正常对照组明显减少,并出现Th1/Th2及Tc1/Tc2漂移呈Th2及Tc2优势现象;胃癌患者外周血记忆性T细胞CD4~+T_(CM)、CD4~+T_(EM)、CD8~+T_(CM)亚群均较正常对照组明显升高,但是在外周主要承担杀伤性效应的CD8~+T_(EM)亚群不但不升高,反而较正常人群略有下降;胃癌患者外周血DC1、DC2及DC1/DC2较正常对照组无明显改变;胃癌患者外周血NK及NKT细胞较正常对照组无明显改变;2.共有效随访68例综合治疗后胃癌患者,COX比例风险模型多因素分析显示:患者年龄、手术类型、临床分期及术后ACI治疗为影响胃癌患者预后的独立因素(P<0.05)。单因素Kaplan-Meier模型分析及Log-Rank检验结果显示患者年龄、手术类型、临床分期及术后早期ACI治疗(手术后14天内)是影响胃癌患者术后预后的相关因素(P<0.05),而患者性别、病理类型、术后化疗、术后ACI治疗次数对患者预后没有显著性影响(P>0.05)。
研究结论:1.流式细胞术检测胃癌患者免疫状态技术平台方法稳定,临床应用性良好;2.胃癌患者预存免疫状态较正常人明显低下,评估患者预存免疫状态并将免疫指标加入胃癌疗效评价体系对确定其治疗方案及疗效评价有着重要意义；3.患者年龄、手术类型、临床分期及术后ACI治疗为影响胃癌患者预后的独立因素,较晚的发病年龄(>50岁)、施行根治性手术、较早的临床分期及术后早期ACI治疗(手术后14天内)可延长术后胃癌患者生存期,而患者性别、病理类型、术后化疗、术后ACI治疗次数对患者预后没有显著性影响。本项研究表明,术后早期免疫活性细胞过继转移治疗可延长胃癌患者手术后生存期,为提高胃癌患者综合治疗水平开创了新的前景。
Background: Gastric cancer is the most common malignant tumor of digestive tract in China. Despite of the development of various treatments such as surgery, chemotherapy, neoadjuvant chemotherapy and radiotherapy, the prognosis of gastric cancer patients at advanced stage still remains poor. The possibility of applying immunotherapy for gastric cancer would therefore be highly desirable. Adoptive cellular immunotherapy (ACI) have therapeutic activity in with high immunogenic tumor such as melanoma and kidney cancer, however, it's still unclear in gastric cancer.
According to tumor immunoediting hypothesis, pre-existing immunity of gastric cancer patients is closely related to onset and progress of tumor and the poor prognosis. Therefore, establishing methods to assess pre-existing immunity and adding immunological parameters into the prognostic evaluation system of gastric cancer are significant to evaluate postoperative therapeutic strategy and efficacy.
The immunological function of early postoperative patients is decreased significantly, and it is not suitable for applying systemic chemotherapy at this point. However, the tumor load in vivo is reduced to minimum. Therefore, it is suggested that early postoperative infusion of multiple immunologicly competent cells, such as DC, CIK and CTL, should improve immune function of patients and achieve more satisfactory results.
Objective: This study was designed to establish methods for assessing pre-existing immunity of gastric cancer patients, establish database and prognostic evaluation system of gastric cancer patients after comprehensive treatment, and observe effect of early postoperative ACI on prognosis of gastric cancer patients.
Methods: 1. The flow cytometric immune function assessing system was established, including detection of peripheral DC, Treg, memory T cells, NK, NKT, Th1/Th2, Tc1/Tc2 cells and intracellular cytokine (IFN-γand IL-4) by four-color flow cytometry; 2. Preliminary analysis of pre-existing immunity of preoperative gastric cancer patients (n=25) and healthy controls (n=25) was performed by detecting subsets of DC1 (Lin~-DR~+CDl11c~+CD123~-), DC2 (Lin~-DR~+CD11c~-CD123~+), NK (CD3~-CD56~+), NKT (CD3~+ CD56~+), Treg (CD4~+CD25~+FOXP3~+), CD4~+T_(CM) (CD4~+CD45RO~+CCR7~+CD45RA~-), CD4~+T_(EM) (CD4~+CD45RO~+CCR7~-CD45RA~-), CD8~+T_(CM) (CD8~+CD45RO~+CCR7~+CD45RA~-), CD8~+T_(EM) (CD8~+CD45RO~+CCR7~-CD45RA~-), Th1 (CD4~+IFN-γ~+), Th2 (CD4~+IL-4~+), Tc1 (CD8~+IFN-γ~+) and Tc2 (CD8~+IL-4~+) cells in peripheral blood; 3. A retrospective database of 93 gastric cancer patients following surgical treatment combined with chemotherapy and/or immunotherapy from December 2004 to March 2008 was constructed firstly. Data were censored at time of death, loss to follow-up or January 1st, 2009. Survival was estimated using the Kaplan-Meier method. The factors affecting the survival time were evaluated by Cox proportional hazard model and Log-Rank test.
Results: 1. The results of preoperative gastric cancer patients show: the CD4~+CD25~+FOXP3~+ Treg of gastric cancer patients were significantly higher than the normal control group (1.993±0.830% Vs 1.229±0.656%, P <0.01); the ratios of Th1/PBL, Tc1/PBL, Th1/Th2 and Tc1/Tc2 in gastric cancer patients were significantly lower than the normal control group (3.047±1.710 % Vs 6.242±4.078 % , 6.393±5.235 % Vs 14.171±8.984 %, 1.215±0.219 % Vs 2.552±2.343 %, 1.306±0.289 % Vs 17.200±25.930 %, P<0.05); the CD4~+T_(CM), CD4~+T_(EM), CD8~+T_(cm) of gastric cancer patients were significantly higher than the normal control group (4.585±2.502% Vs 2.765±1.942%, 18.682±7.374% Vs 13.032±4.059 %, 0.455±0.472% Vs 0.127±0.165%, P <0.05), but there was no significant difference of CD8~+T_(EM) between them (8.379±3.431% Vs 8.733±3.048%, P> 0.05); there was no significant difference of DC1, DC2 and DC1/DC2 in peripheral blood between gastric cancer patients and normal control (0.201±0.095% Vs 0.198±0.087%, 0.081±0.032% Vs 0.093±0.046%, 2.693±1.636% Vs 2.561±1.486%, P> 0.05); there was no significant difference of NK and NKT in peripheral blood between gastric cancer patients and normal control (19.209±14.116% Vs 20.306±8.844%, 8.481±5.378% Vs 6.156±3.934%, P> 0.05). 2. Complete follow-up data were obtained from 68 cases of patients, majority of who were advanced stage ones. In total, 35 patients died, giving median survival time of 21 months. The estimated 3-year overall survival was 36%. In univariate analysis, age, clinical stage, type of surgery and early postoperative adoptive immunotherapy (less than 14 days after operation) were significant prognostic factors related to overall survival time (P <0.05). Gender, histopathologically diffuse type, adjuvant chemotherapy and numbers of immunotherapy were found to have no effect on survival (P> 0.05). In multivariate analysis, age, radical surgery, clinical stage, early postoperative adoptive immunotherapy (less than 14 days after operation) were found to be the statistically significant prognostic factors related to survival (P <0.05).
Conclusion: 1. The flow cytometric immune function assay was a stable method for assessing pre-existing immunity of gastric cancer patients; 2. The pre-existing immunity was poor in preoperative gastric cancer patients, which might be related to the onset and progress of tumor and the poor prognosis. Immunological parameters might be useful predictors to evaluate prognosis of gastric cancer patients; 3. The factors including age, clinical stage, radical surgery and early postoperative adoptive immunotherapy had significant effect on survival of postoperative gastric cancer patients. Early postoperative adoptive immunotherapy couid be a beneficial adjuvant therapy to improve clinical outcomes of gastric cancer patients.
引文
1. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995, 155(3):1151-1164.
2. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001, 27(1): 68-73.
3. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004, 4(9): 665-674.
4. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, et al. Immunologic tolerance maintained by CD25~+ CD4~+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001, 182:18-32.
5. 王凌云,黄开红,闵军,等.胃癌患者外周血调节性T细胞的多种细胞因子水平的检测及其意义.中华实验外科杂志.2006,23:1375-1377.
6. Karagoz B, Bilgi O, Gumus M, et al. CD8~+CD28~- cells and CD4~+CD25~+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients. Med Oncol. 2009 Jan 16.
7. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 2008, 21(12): 1527-1532.
8. Ohara M, Yamaguchi Y, Matsuura K, et al. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother. 2009, 58(3): 441-447.
9. Perrone G, Ruffini PA, Catalano V, et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer. 2008, 44(13): 1875-1882.
10. Yokokawa J, Cereda V, Remondo C, et al. Enhanced functionality of CD4+CD25(high)FoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer. Clin Cancer Res. 2008, 14(4): 1032-1040.
11. Ling KL, Pratap SE, Bates GJ, et al. Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun. 2007 Mar 28; 7:7.
12. Clarke SL, Berts GJ, Plant A, et al. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS ONE. 2006 Dec 27; 1 :el29.
13. Viehl CT, Moore TT, Liyanage UK, Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol. 2006, 13(9): 1252-1258.
14. Li H, Yu JP, Cao S, et al. CD4 +CD25 + regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol. 2007, 27(3): 317-326.
15. Perrone G, Ruffini PA, Catalano V, et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer. 2008, 44:1875-1882.
16. Kawaida H, Kono K, Takahashi A, et al. Distribution of CD4~+CD25~(high) regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res. 2005, 124:151-157.
17. 刘海,郑维,李远明,等.大肠癌患者外周血调节性T细胞的检测及临床意义.中华实验外科杂志.2007,24:626-627.
18. Steinman RM, Cohn ZA. Identification of a novel cell type in tissue distribution. J Exp Med. 1973, 137:1142-1162.
19. Osada T, Clay T, Hobeika A, Lyerly HK, Morse MA. NK cell activation by dendritic cell vaccine:a mechanism of action for clinical activity.Cancer Immunol Immunother.2005,5:1-10.
20.Kadowaki N,Antonenko S,Ho S,et al.Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells.J Exp Med.2001,193:1221-1226.
21.Steinman RM.The dendritic cell system and its role in immunogenicity.Annu Rev Immunol.1999,9:271-296.
22.Banchereau J,Briere F,Caux C,et al.Immunobiology of dendritic cells.Annu Rev Immunol.2000,18:767-811.
23.Banchereau J,Steinman RM.Dendritic cells and the control of immunity.Nature.1998,392:245-252.
24.Wu L,Dakic A.Development of dendritic cell system.Cell Mol Immunol.2004,1:112-118.
25.Ito T,Amakawa R,Inaba M,et al.Differential regulation of human blood dendritic cell subsets by IFNs.J Immunol.2001,166:2961-2969
26.Gong J,Nikrui N,Chen D,et al.Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity.J Immunol.2000,165(3):1705-1711.
27.Shi L,Kraut RP,Aebersold R,et al.A natural killer cell granule protein that induces DNA fragmentation and apoptosis.J Exp Med.1992,175(2):553-566.
28.Huang HL,Wu BY,You WD,et al.Influence of dendritic cell infiltration on prognosis and biologic characteristics of progressing gastric cancer.Zhonghua Zhong Liu Za Zhi.2003,25(5):468-471.
29.Shimamura H,Cumberland R,Hiroisni K,et al.Murine Dendritic Cell-Induced Tumor Apoptosis is Partially Mediated by NitricOxide.J Immunother.2002,25(3):226-234.
30.Lu G,Janjic BM,Janjic J,et al.Innate direct anticancer effector function of human immature dendritic cells.Ⅱ.Role of TNF,lymphotoxin-alpha(1)beta(2),Fas ligand,and TNF-related apoptosis-inducing ligand.J Immunol.2002,168(4):1831-1839.
31.Chapoval Al,Tamada K,Chen L.In vitro growth inhibition of a broad spectrum of tumor cell lines by activated human dendritic cells.Blood.2000,95(7):2346-2351.
32.Fernandez NC,Flament C,Crepineau F,et al.Dendritic cells(DC)promote natural killer(NK)cell functions:dynamics of the human DC/NKcell cross talk.Eur Cytokine Netw.2002,13(1):17-27.
33.Leplina OY,Stupak VV,Kozlov YP,et al.Use of interferon-alpha-induced dendritic cells in the therapy of patients with malignant brain gliomas.Bull Exp Biol Med.2007,143(4):528-534.
34.Wei H,Wang H,Lu B,et al.Cancer immunotherapy using in vitro genetically modified targeted dendritic cells.Cancer Res.2008,68(10):3854-3862.
35.Engleman EG.Dendritic cell-based cancer immuno therapy.Sem in Onco 1.2003,30(3 Supp 18):23-29.
36.Banchereau J,Steinman RM.Dendritic cells and the control of immunity.Nature.1998,392(6673):245-252.
37.Dallal R,Lotzem M.The dendritic cell and human cancer vaccines.Curr Opin Immunul.2000,12(5):583-588.
38.Lawarence F,Edgar G.Dendritic cells in cancer immunotherapy.Annu Rer Immunol.2000,18(2):245-273.
39.Farrar JD,Asnagli H,Murphy KM.T helper subset development:roles of instruction,selection,and transcription.J Clin Invest.2002,109:431-435.
40.Glimcher LH,Murphy KM.Lineage commitment in the immune system:the T helper lymphocyte grows up.Genes Dev.2000,14:1693-1711.
41. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003, 8: 223-246.
42. Naldini A, Pucci A, Bernini C, et al. Regulation of angiogenesis by Th1- and Th2-type cytokines. Curr Pharm Des. 2003, 9: 511-519.
43. Ito N, Suzuki Y, Taniguchi Y, et al. Prognostic significance of T helper 1 and 2 and T cytotoxic 1 and 2 cells in patients with non-small cell lung cancer. Anticancer Res. 2005, 25: 2027-2031.
44. Yamazaki K, Yano T, Kameyama T, et al. Clinical significance of serum TH1/TH2 cytokines in patients with pulmonary adenocarcinoma. Surgery. 2002, 131: S236-241.
45. Li R, Rüttinger D, Li R, et al. Analysis of the immunological microenvironment at the tumor site in patients with non-small cell lung cancer. Langenbecks Arch Surg. 2003, 388: 406-412.
46. Chechlinska M, Duma A, Swierkowska K, et al. Sera of lung cancer patients affect the release of Th1, Th2 and monocyte-derived cytokines, and the expression of IL-2Ralpha by normal, stimulated mononuclear cells. Cell Mol Biol Lett. 2004, 9:69-81.
47. Woodland DL. Cell-mediated immunity to respiratory virus infections. Curr Opin Immunol. 2003, 15 (4): 430 - 435.
48. 吴长有.记忆CD8~+T细胞亚群在感染和肿瘤免疫应答中的作用.细胞与分子免疫学杂志.2006,22(3):273-275
49. Badovinac VP, Messingham KA, Jabbari A, et al. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med. 2005 Jul; 11(7):748-756.
50. Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005, 17 (3):326-332.
51. Jackson SS, Schmitz JE, Kuroda MJ, et al. Evaluation of CD62L expression as a marker for vaccine-elicited memory cytotoxic T lymphocytes.Immunology.2005,116(4):443-453.
52.Willinger T,Freeman T,Hasegawa H,et al.Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets.J Immunol.2005,175(9):5895-5903.
53.Perret R,Ronchese F.Memory T cells in cancer immunotherapy:which CD8 T-cell population provides the best protection against tumours? Tissue Antigens.2008,72(3):187-94.
54.Fujii S,Shimizu K,Hemmi H,et al.Glycolipid alpha-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice.Proc Natl Acad Sci USA.2006,103(30):11252-11257.
55.Ishikawa A,Motohashi S,Ishikawa E,et al.A phase I study of alpha-galactosylceramide(KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer.Clin Cancer Res.2005,11(5):1910-1917.
56.Chang DH,Osman K,Connolly J,et al.Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients.J Exp Med.2005,201(9):1503-1517
1 Hundahl SA,Phillips JL,Menck HR.The National Cancer Data Base Report on poor survival of U.S.gastric carcinoma patients treated with gastrectomy.Fifth Edition American Joint Committee on Cancer staging,proximal disease,and the "different disease" hypothesis.Cancer.2000,88(4):921-932.
2 Faivre J,Forman D,Esteve J,et al.Survival of patients with oesophageal and gastric cancers in Europe.Eur J Cancer.1998,34(14):2167-2175.
3 Shiraishi N,Inomata M,Osawa N,et al.Early and late recurrence after gastrectomy for gastric carcinoma.Univariate and multivariate analyses.Cancer.2000,89(2):255-261.
4 Gasparini G,Inelmen EM,Enzi G,et al.Clinical and prognostic aspects of gastric carcinoma in the elderly.J Gastrointest Surg.2006,10(3):395-401.
5 Ghiandoni G,Rocchi MB,Signoretti P,et al.Prognostic factors in gastric cancer evaluated by using Cox regression model.Minerva Chir.1998,53(6):497-504.
6 Wu CW,Lin YY,Chen GD,et al.Serum anti-p53 antibodies in gastric adenocarcinoma patients are associated with poor prognosis,lymph node metastasis and poorly differentiated nuclear grade.Br J Cancer.1999,80(3-4):483-488.
7 Maehara Y,Tomoda M,Hasuda S,et al.Prognostic value of p53 protein expression for patients with gastric cancer-a multivariate analysis.Br J Cancer.1999,79(7-8):1255-1261..
8 Park DI,Yun JW,Park JH,et al.HER-2/neu amplification is an independent prognostic factor in gastric cancer.Dig Dis Sci.2006,51(8):1371-1379.
9 Yoo CH,Noh SH,Kim H,et al.Prognostic significance of CD44 and nm23 expression in patients with stage II and stage IIIA gastric carcinoma.J Surg Oncol.1999,71(1):22-28.
10 Alici S,Kaya S,Izmirli M,et al.Analysis of survival factors in patients with advanced-stage gastric adenocarcinoma.Med Sci Monit.2006,12(5):CR221-229.
11 Koea IB,Karpeh MS,Brennan MF.Gastric cancer in young patients:demographic,clinicopathological,and prognostic factors in 92 patients.Ann Surg Oncol.2000,7(5):346-351.
12 Park JC,Lee YC,Kim JH,et al.Clinicopathological aspects and prognostic value with respect to age:An analysis of 3,362 consecutive gastric cancer patients.J Surg Oncol.2009 Apr 3.[Epub ahead of print]
13 Lee JH,Ryu KW,Lee JS,et al.Decisions for extent of gastric surgery in gastric cancer patients:younger patients require more attention than the elderly.J Surg Oncol.2007,95(6):485-490.
14 Fujii K,Isozaki H,Okajima K,et al.Clinical evaluation of lymph node metastasis in gastric cancer defined by the fifth edition of the TNM classification in comparison with the Japanese system.Br J Surg.1999,86(5):685-689.
15 Hayashi H,Ochiai T,Suzuki T,et al.Superiority of a new UICC-TNM staging system for gastric carcinoma.Surgery.2000,127(2):129-135.
16 Cimerman M,Repse S,Jelenc F,et al.Comparison of Lauren's,Ming's and WHO histological classifications of gastric cancer as a prognostic factor for operated patients.Int Surg.1994,79(1):27-32.
17 Gastric Cancer Surgical Study Group.Nakajima T,Nashimoto A,Kitamura M,et al.Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer:a randomised trial.Lancet.1999,354(9175):273-277.
18 Leong CN,Chung HT,Lee KM,et al.Outcomes of adjuvant chemoradiotherapy after a radical gastrectomy and a D2 node dissection for gastric adenocarcinoma.Cancer J.2008,14(4):269-275.
19 Hermans J,Bonenkamp JJ,Boon MC,et al.Adjuvant therapy after curative resection for gastric cancer:meta-analysis of randomized trials.J Clin Oncol.1993,11(8):1441-1447
20 Earle CC,Maroun JA.Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients:revisiting a meta-analysis of randomised trials.Eur J Cancer.1999,35(7):1059-1064.
21 Mari E,Floriani I,Tinazzi A,et al.Efficacy of adjuvant chemotherapy after curative resection for gastric cancer:a meta-analysis of published randomised trials.A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'ApparatoDigerente).Ann Oncol.2000,11:837-843.
22 Panzini I,Gianni L,Fattori PP,et al.Adjuvant chemotherapy in gastric cancer:a meta-analysis of randomized trials and a comparison with previous meta-analyses.Tumori.2002,88(1):21-27.
23 Janunger KG,Hafstrom L,Glimelius B.Chemotherapy in gastric cancer:a review and updated meta-analysis.Eur J Surg.2002,168(11):597-608.
24 Liu TS,Wang Y,Chen SY,et al.An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer.Eur J Surg Oncol.2008,34(11):1208-1216.
25 Bleiberg H,Sahmoud T,Di Leo A,et al.Adequate number of patients are needed to evaluate adjuvant treatment in gastric cancer.J Clin Oncol.1998,16(11):3714.
26 Lau R,Wang F,Jeffery Q et al.Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma.J Immunother.2001,24:66-78.
27 Mayordomo JI,Andres R,Isla MD,et al.Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.Tumori.2007,93(1):26-30.
28 Jung Han Kim,Yoon Lee,Yong-Soo Bae,et al.Phase Ⅰ/Ⅱ study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma.Clinical Immunology.2007,125,257-267
29 Jiang J,Xu N,Wu C,et al.Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells.Anticancer Res.2006,26(3B):2237-2242.
30 Toh U,Fujii T,Mishima M,et al.Conventional chemotherapy combined with the repetitive immune cell transfer for patients with refractory advanced gastric cancer.Gan To Kagaku Ryoho.2007,34(12):1931-1933.
31 Kono K,Takahashi A,Ichihara F,et al.Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer:a randomized trial.Clin Cancer Res.2002,8(6):1767-1771.
1.Osada T,Clay T,Hobeika A,Lyerly HK,Morse MA.NK cell activation by dendritic cell vaccine:a mechanism of action for clinical activity.Cancer Immunol Immunother.2005;5:1-10.
2.Kadowaki N,Antonenko S,Ho S,et al.Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells.J Exp Med.2001;193:1221-1226.
3.Cai YQ Fang DC,Chen L,et al.Dendritic cells reconstituted with a human heparanase gene induce potent cytotoxic T-cell responses against gastric tumor cells in vitro.Tumour Biol.2007;28(4):238-46.
4.Cai YQ Fang DC,Chen L,et al.Immune response of heparinase gene modified dendritic cell-based vaccine on gastric cancer cells.Zhonghua Yi Xue Za Zhi.2006 Nov 28;86(44):3122-7
5.Sun HW,Tang C,Tang QB,et al.Study of immunological effect of dendritic cell transfected with survivin gene on the specific anti-alimentary tract tumor.Zhonghua Wai KeZaZhi.2005 Mar 1;43(5):313-6.
6.Zhang K,Yu PW,GAO PF,Rao Y Inhibitive effects of gastric cancer cell-dendritic cell fusion vaccine on tumorcell proliferation cycle.Zhonghua Wei Chang Wai Ke Za Zhi.2006 Jul;9(4):345-8.
7.Oosterling SJ,Mels AK,Geijtenbeek TB,et al.Preoperative granulocyte/macrophage colony-stimulating factor (GM-CSF) increases hepatic dendritic cell numbers and clustering with lymphocytes in colorectal cancer patients.Immunobiology.2006;211(6-8):641-9.
8.Yamaguchi Y,Ohta K,Kawabuchi Y,et al.Feasibility study of adoptive immunotherapy for metastatic lung tumors using peptide-pulsed dendritic cell-activated killer (PDAK) cells.Anticancer Res.2005 May-Jun;25(3c):2407-15.
9.Morse MA,Clay TM,Hobeika AC,et al.Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.Clin Cancer Res.2005 Apr 15;11(8):3017-24.
10.Mayordomo JI,Andres R,Isla MD,et al.Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.Tumori.2007;93(1):26-30.
11.Terando A,Roessler B,Mule J:Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector.Cancer Gene Ther,11:165-173,2004.
12.Sangiolo D,Martinuzzi E,Todorovic M,et al.Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells:implications for their infusion across major HLA barriers.Int Immunol.2008 Jul;20(7):841-8.
13.Jiang J,Xu N,Wu C,et al.Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells.Anticancer Res.2006 May-Jun;26(3B):2237-42.
14.Toh U,Fujii T,Mishima M,et al.Conventional chemotherapy combined with the repetitive immune cell transfer for patients with refractory advanced gastric cancer.Gan To Kagaku Ryoho.2007 Nov;34(12):1931-3.
2. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001, 27(1): 68-73.
3. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004, 4(9): 665-674.
4. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, et al. Immunologic tolerance maintained by CD25~+ CD4~+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001, 182:18-32.
5. 王凌云,黄开红,闵军,等.胃癌患者外周血调节性T细胞的多种细胞因子水平的检测及其意义.中华实验外科杂志.2006,23:1375-1377.
6. Karagoz B, Bilgi O, Gumus M, et al. CD8~+CD28~- cells and CD4~+CD25~+ regulatory T cells in the peripheral blood of advanced stage lung cancer patients. Med Oncol. 2009 Jan 16.
7. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 2008, 21(12): 1527-1532.
8. Ohara M, Yamaguchi Y, Matsuura K, et al. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother. 2009, 58(3): 441-447.
9. Perrone G, Ruffini PA, Catalano V, et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer. 2008, 44(13): 1875-1882.
10. Yokokawa J, Cereda V, Remondo C, et al. Enhanced functionality of CD4+CD25(high)FoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer. Clin Cancer Res. 2008, 14(4): 1032-1040.
11. Ling KL, Pratap SE, Bates GJ, et al. Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun. 2007 Mar 28; 7:7.
12. Clarke SL, Berts GJ, Plant A, et al. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS ONE. 2006 Dec 27; 1 :el29.
13. Viehl CT, Moore TT, Liyanage UK, Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol. 2006, 13(9): 1252-1258.
14. Li H, Yu JP, Cao S, et al. CD4 +CD25 + regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J Clin Immunol. 2007, 27(3): 317-326.
15. Perrone G, Ruffini PA, Catalano V, et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer. 2008, 44:1875-1882.
16. Kawaida H, Kono K, Takahashi A, et al. Distribution of CD4~+CD25~(high) regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res. 2005, 124:151-157.
17. 刘海,郑维,李远明,等.大肠癌患者外周血调节性T细胞的检测及临床意义.中华实验外科杂志.2007,24:626-627.
18. Steinman RM, Cohn ZA. Identification of a novel cell type in tissue distribution. J Exp Med. 1973, 137:1142-1162.
19. Osada T, Clay T, Hobeika A, Lyerly HK, Morse MA. NK cell activation by dendritic cell vaccine:a mechanism of action for clinical activity.Cancer Immunol Immunother.2005,5:1-10.
20.Kadowaki N,Antonenko S,Ho S,et al.Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells.J Exp Med.2001,193:1221-1226.
21.Steinman RM.The dendritic cell system and its role in immunogenicity.Annu Rev Immunol.1999,9:271-296.
22.Banchereau J,Briere F,Caux C,et al.Immunobiology of dendritic cells.Annu Rev Immunol.2000,18:767-811.
23.Banchereau J,Steinman RM.Dendritic cells and the control of immunity.Nature.1998,392:245-252.
24.Wu L,Dakic A.Development of dendritic cell system.Cell Mol Immunol.2004,1:112-118.
25.Ito T,Amakawa R,Inaba M,et al.Differential regulation of human blood dendritic cell subsets by IFNs.J Immunol.2001,166:2961-2969
26.Gong J,Nikrui N,Chen D,et al.Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity.J Immunol.2000,165(3):1705-1711.
27.Shi L,Kraut RP,Aebersold R,et al.A natural killer cell granule protein that induces DNA fragmentation and apoptosis.J Exp Med.1992,175(2):553-566.
28.Huang HL,Wu BY,You WD,et al.Influence of dendritic cell infiltration on prognosis and biologic characteristics of progressing gastric cancer.Zhonghua Zhong Liu Za Zhi.2003,25(5):468-471.
29.Shimamura H,Cumberland R,Hiroisni K,et al.Murine Dendritic Cell-Induced Tumor Apoptosis is Partially Mediated by NitricOxide.J Immunother.2002,25(3):226-234.
30.Lu G,Janjic BM,Janjic J,et al.Innate direct anticancer effector function of human immature dendritic cells.Ⅱ.Role of TNF,lymphotoxin-alpha(1)beta(2),Fas ligand,and TNF-related apoptosis-inducing ligand.J Immunol.2002,168(4):1831-1839.
31.Chapoval Al,Tamada K,Chen L.In vitro growth inhibition of a broad spectrum of tumor cell lines by activated human dendritic cells.Blood.2000,95(7):2346-2351.
32.Fernandez NC,Flament C,Crepineau F,et al.Dendritic cells(DC)promote natural killer(NK)cell functions:dynamics of the human DC/NKcell cross talk.Eur Cytokine Netw.2002,13(1):17-27.
33.Leplina OY,Stupak VV,Kozlov YP,et al.Use of interferon-alpha-induced dendritic cells in the therapy of patients with malignant brain gliomas.Bull Exp Biol Med.2007,143(4):528-534.
34.Wei H,Wang H,Lu B,et al.Cancer immunotherapy using in vitro genetically modified targeted dendritic cells.Cancer Res.2008,68(10):3854-3862.
35.Engleman EG.Dendritic cell-based cancer immuno therapy.Sem in Onco 1.2003,30(3 Supp 18):23-29.
36.Banchereau J,Steinman RM.Dendritic cells and the control of immunity.Nature.1998,392(6673):245-252.
37.Dallal R,Lotzem M.The dendritic cell and human cancer vaccines.Curr Opin Immunul.2000,12(5):583-588.
38.Lawarence F,Edgar G.Dendritic cells in cancer immunotherapy.Annu Rer Immunol.2000,18(2):245-273.
39.Farrar JD,Asnagli H,Murphy KM.T helper subset development:roles of instruction,selection,and transcription.J Clin Invest.2002,109:431-435.
40.Glimcher LH,Murphy KM.Lineage commitment in the immune system:the T helper lymphocyte grows up.Genes Dev.2000,14:1693-1711.
41. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003, 8: 223-246.
42. Naldini A, Pucci A, Bernini C, et al. Regulation of angiogenesis by Th1- and Th2-type cytokines. Curr Pharm Des. 2003, 9: 511-519.
43. Ito N, Suzuki Y, Taniguchi Y, et al. Prognostic significance of T helper 1 and 2 and T cytotoxic 1 and 2 cells in patients with non-small cell lung cancer. Anticancer Res. 2005, 25: 2027-2031.
44. Yamazaki K, Yano T, Kameyama T, et al. Clinical significance of serum TH1/TH2 cytokines in patients with pulmonary adenocarcinoma. Surgery. 2002, 131: S236-241.
45. Li R, Rüttinger D, Li R, et al. Analysis of the immunological microenvironment at the tumor site in patients with non-small cell lung cancer. Langenbecks Arch Surg. 2003, 388: 406-412.
46. Chechlinska M, Duma A, Swierkowska K, et al. Sera of lung cancer patients affect the release of Th1, Th2 and monocyte-derived cytokines, and the expression of IL-2Ralpha by normal, stimulated mononuclear cells. Cell Mol Biol Lett. 2004, 9:69-81.
47. Woodland DL. Cell-mediated immunity to respiratory virus infections. Curr Opin Immunol. 2003, 15 (4): 430 - 435.
48. 吴长有.记忆CD8~+T细胞亚群在感染和肿瘤免疫应答中的作用.细胞与分子免疫学杂志.2006,22(3):273-275
49. Badovinac VP, Messingham KA, Jabbari A, et al. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med. 2005 Jul; 11(7):748-756.
50. Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005, 17 (3):326-332.
51. Jackson SS, Schmitz JE, Kuroda MJ, et al. Evaluation of CD62L expression as a marker for vaccine-elicited memory cytotoxic T lymphocytes.Immunology.2005,116(4):443-453.
52.Willinger T,Freeman T,Hasegawa H,et al.Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets.J Immunol.2005,175(9):5895-5903.
53.Perret R,Ronchese F.Memory T cells in cancer immunotherapy:which CD8 T-cell population provides the best protection against tumours? Tissue Antigens.2008,72(3):187-94.
54.Fujii S,Shimizu K,Hemmi H,et al.Glycolipid alpha-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice.Proc Natl Acad Sci USA.2006,103(30):11252-11257.
55.Ishikawa A,Motohashi S,Ishikawa E,et al.A phase I study of alpha-galactosylceramide(KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer.Clin Cancer Res.2005,11(5):1910-1917.
56.Chang DH,Osman K,Connolly J,et al.Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients.J Exp Med.2005,201(9):1503-1517
1 Hundahl SA,Phillips JL,Menck HR.The National Cancer Data Base Report on poor survival of U.S.gastric carcinoma patients treated with gastrectomy.Fifth Edition American Joint Committee on Cancer staging,proximal disease,and the "different disease" hypothesis.Cancer.2000,88(4):921-932.
2 Faivre J,Forman D,Esteve J,et al.Survival of patients with oesophageal and gastric cancers in Europe.Eur J Cancer.1998,34(14):2167-2175.
3 Shiraishi N,Inomata M,Osawa N,et al.Early and late recurrence after gastrectomy for gastric carcinoma.Univariate and multivariate analyses.Cancer.2000,89(2):255-261.
4 Gasparini G,Inelmen EM,Enzi G,et al.Clinical and prognostic aspects of gastric carcinoma in the elderly.J Gastrointest Surg.2006,10(3):395-401.
5 Ghiandoni G,Rocchi MB,Signoretti P,et al.Prognostic factors in gastric cancer evaluated by using Cox regression model.Minerva Chir.1998,53(6):497-504.
6 Wu CW,Lin YY,Chen GD,et al.Serum anti-p53 antibodies in gastric adenocarcinoma patients are associated with poor prognosis,lymph node metastasis and poorly differentiated nuclear grade.Br J Cancer.1999,80(3-4):483-488.
7 Maehara Y,Tomoda M,Hasuda S,et al.Prognostic value of p53 protein expression for patients with gastric cancer-a multivariate analysis.Br J Cancer.1999,79(7-8):1255-1261..
8 Park DI,Yun JW,Park JH,et al.HER-2/neu amplification is an independent prognostic factor in gastric cancer.Dig Dis Sci.2006,51(8):1371-1379.
9 Yoo CH,Noh SH,Kim H,et al.Prognostic significance of CD44 and nm23 expression in patients with stage II and stage IIIA gastric carcinoma.J Surg Oncol.1999,71(1):22-28.
10 Alici S,Kaya S,Izmirli M,et al.Analysis of survival factors in patients with advanced-stage gastric adenocarcinoma.Med Sci Monit.2006,12(5):CR221-229.
11 Koea IB,Karpeh MS,Brennan MF.Gastric cancer in young patients:demographic,clinicopathological,and prognostic factors in 92 patients.Ann Surg Oncol.2000,7(5):346-351.
12 Park JC,Lee YC,Kim JH,et al.Clinicopathological aspects and prognostic value with respect to age:An analysis of 3,362 consecutive gastric cancer patients.J Surg Oncol.2009 Apr 3.[Epub ahead of print]
13 Lee JH,Ryu KW,Lee JS,et al.Decisions for extent of gastric surgery in gastric cancer patients:younger patients require more attention than the elderly.J Surg Oncol.2007,95(6):485-490.
14 Fujii K,Isozaki H,Okajima K,et al.Clinical evaluation of lymph node metastasis in gastric cancer defined by the fifth edition of the TNM classification in comparison with the Japanese system.Br J Surg.1999,86(5):685-689.
15 Hayashi H,Ochiai T,Suzuki T,et al.Superiority of a new UICC-TNM staging system for gastric carcinoma.Surgery.2000,127(2):129-135.
16 Cimerman M,Repse S,Jelenc F,et al.Comparison of Lauren's,Ming's and WHO histological classifications of gastric cancer as a prognostic factor for operated patients.Int Surg.1994,79(1):27-32.
17 Gastric Cancer Surgical Study Group.Nakajima T,Nashimoto A,Kitamura M,et al.Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer:a randomised trial.Lancet.1999,354(9175):273-277.
18 Leong CN,Chung HT,Lee KM,et al.Outcomes of adjuvant chemoradiotherapy after a radical gastrectomy and a D2 node dissection for gastric adenocarcinoma.Cancer J.2008,14(4):269-275.
19 Hermans J,Bonenkamp JJ,Boon MC,et al.Adjuvant therapy after curative resection for gastric cancer:meta-analysis of randomized trials.J Clin Oncol.1993,11(8):1441-1447
20 Earle CC,Maroun JA.Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients:revisiting a meta-analysis of randomised trials.Eur J Cancer.1999,35(7):1059-1064.
21 Mari E,Floriani I,Tinazzi A,et al.Efficacy of adjuvant chemotherapy after curative resection for gastric cancer:a meta-analysis of published randomised trials.A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'ApparatoDigerente).Ann Oncol.2000,11:837-843.
22 Panzini I,Gianni L,Fattori PP,et al.Adjuvant chemotherapy in gastric cancer:a meta-analysis of randomized trials and a comparison with previous meta-analyses.Tumori.2002,88(1):21-27.
23 Janunger KG,Hafstrom L,Glimelius B.Chemotherapy in gastric cancer:a review and updated meta-analysis.Eur J Surg.2002,168(11):597-608.
24 Liu TS,Wang Y,Chen SY,et al.An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer.Eur J Surg Oncol.2008,34(11):1208-1216.
25 Bleiberg H,Sahmoud T,Di Leo A,et al.Adequate number of patients are needed to evaluate adjuvant treatment in gastric cancer.J Clin Oncol.1998,16(11):3714.
26 Lau R,Wang F,Jeffery Q et al.Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma.J Immunother.2001,24:66-78.
27 Mayordomo JI,Andres R,Isla MD,et al.Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.Tumori.2007,93(1):26-30.
28 Jung Han Kim,Yoon Lee,Yong-Soo Bae,et al.Phase Ⅰ/Ⅱ study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma.Clinical Immunology.2007,125,257-267
29 Jiang J,Xu N,Wu C,et al.Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells.Anticancer Res.2006,26(3B):2237-2242.
30 Toh U,Fujii T,Mishima M,et al.Conventional chemotherapy combined with the repetitive immune cell transfer for patients with refractory advanced gastric cancer.Gan To Kagaku Ryoho.2007,34(12):1931-1933.
31 Kono K,Takahashi A,Ichihara F,et al.Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer:a randomized trial.Clin Cancer Res.2002,8(6):1767-1771.
1.Osada T,Clay T,Hobeika A,Lyerly HK,Morse MA.NK cell activation by dendritic cell vaccine:a mechanism of action for clinical activity.Cancer Immunol Immunother.2005;5:1-10.
2.Kadowaki N,Antonenko S,Ho S,et al.Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells.J Exp Med.2001;193:1221-1226.
3.Cai YQ Fang DC,Chen L,et al.Dendritic cells reconstituted with a human heparanase gene induce potent cytotoxic T-cell responses against gastric tumor cells in vitro.Tumour Biol.2007;28(4):238-46.
4.Cai YQ Fang DC,Chen L,et al.Immune response of heparinase gene modified dendritic cell-based vaccine on gastric cancer cells.Zhonghua Yi Xue Za Zhi.2006 Nov 28;86(44):3122-7
5.Sun HW,Tang C,Tang QB,et al.Study of immunological effect of dendritic cell transfected with survivin gene on the specific anti-alimentary tract tumor.Zhonghua Wai KeZaZhi.2005 Mar 1;43(5):313-6.
6.Zhang K,Yu PW,GAO PF,Rao Y Inhibitive effects of gastric cancer cell-dendritic cell fusion vaccine on tumorcell proliferation cycle.Zhonghua Wei Chang Wai Ke Za Zhi.2006 Jul;9(4):345-8.
7.Oosterling SJ,Mels AK,Geijtenbeek TB,et al.Preoperative granulocyte/macrophage colony-stimulating factor (GM-CSF) increases hepatic dendritic cell numbers and clustering with lymphocytes in colorectal cancer patients.Immunobiology.2006;211(6-8):641-9.
8.Yamaguchi Y,Ohta K,Kawabuchi Y,et al.Feasibility study of adoptive immunotherapy for metastatic lung tumors using peptide-pulsed dendritic cell-activated killer (PDAK) cells.Anticancer Res.2005 May-Jun;25(3c):2407-15.
9.Morse MA,Clay TM,Hobeika AC,et al.Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.Clin Cancer Res.2005 Apr 15;11(8):3017-24.
10.Mayordomo JI,Andres R,Isla MD,et al.Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.Tumori.2007;93(1):26-30.
11.Terando A,Roessler B,Mule J:Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector.Cancer Gene Ther,11:165-173,2004.
12.Sangiolo D,Martinuzzi E,Todorovic M,et al.Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells:implications for their infusion across major HLA barriers.Int Immunol.2008 Jul;20(7):841-8.
13.Jiang J,Xu N,Wu C,et al.Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells.Anticancer Res.2006 May-Jun;26(3B):2237-42.
14.Toh U,Fujii T,Mishima M,et al.Conventional chemotherapy combined with the repetitive immune cell transfer for patients with refractory advanced gastric cancer.Gan To Kagaku Ryoho.2007 Nov;34(12):1931-3.
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