gp100209–2M Peptide Immunization of Human Lymphocyte Antigen-A2+ Stage I-III Melanoma Patients Induces Significant Increase in Antigen-Specific Effector and Long-Term Memory CD8+ T Cells
gp100209–2M Peptide Immunization of Human Lymphocyte Antigen-A2+ Stage I-III Melanoma Patients Induces Significant Increase in Antigen-Specific Effector and Long-Term Memory CD8+ T Cells
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gp100209–2M 肽免疫人类淋巴细胞抗原 A2+ I-III 期黑色素瘤患者可诱导抗原特异性效应细胞和长期记忆 CD8+ T 细胞显着增加
作者：
E. Walker;D. Haley;William L. Miller;K. Floyd;K. P. Wisner;Nelson Sanjuan;H. Maecker;P. Romero;Hong;W. Alvord;John W. Smith;B. Fox;W. Urba
35名HLA-A2+的I-III期黑色素瘤患者在6个月内多次接种在Montanide佐剂中乳化的修饰的黑色素瘤肽gp 100209 - 2 M。疫苗接种前和接种后外周血单核细胞（PBMC）的直接体外gp 100209 - 2 M四聚体分析表明，35例可评价患者中有33例在免疫后四聚体+CD 8 + T细胞的频率显著增加（中位数，0.36%;范围，0.05-8.9%）。在短暂的gp 100209 - 2 M体外活化后，对接种后PBMC进行的离体IFN-γ细胞因子流式细胞术分析显示，对于所有研究的患者，四聚体+CD 8 + T细胞产生IFN-γ;然而，一些患者具有显著数量的四聚体+ IFN-γ− CD 8 +T细胞，表明功能性无能。此外，对34名患者的疫苗接种前和疫苗接种后PBMC进行8天gp 100209 - 2 M体外刺激（IVS）导致四聚体+CD 8 + T细胞从疫苗接种后细胞显著扩增，并且在用天然或修饰的gp 100肽再刺激后，通过IFN-γ细胞因子流式细胞术分析，这些IVS四聚体+CD 8 + T细胞具有功能应答。然而，对疫苗接种后IVS扩增的CD 8 + T细胞的相关功能和表型分析证实了几名患者中功能无反应性gp 100209 - 2 M-四聚体+CD 8 + T细胞的增殖，并且还表明了gp 100209 - 2 M刺激的T细胞增殖的患者间差异。对来自代表性患者的冻存疫苗接种后PBMC进行流式细胞术分析显示，大多数四聚体+CD 8 + T细胞（78.1 ± 4.2%）具有“效应子”（CD 45 RA+/CCR 7 −）或“效应子记忆”表型（CD 45 RA −/CCR 7 −）。值得注意的是，对疫苗治疗后12-24个月收集的PBMC的分析证明了具有高增殖潜力的gp 100209 - 2 M特异性记忆CD 8 + T细胞的持久存在。总体而言，本报告表明，在接种MHC I类限制性黑色素瘤肽后，切除的非转移性黑色素瘤患者可以产生显著的抗原特异性CD 8 + T细胞免疫应答，并具有功能完整的记忆成分。数据进一步支持在相关的离体和IVS设置中组合使用四聚体结合和功能测定作为癌症疫苗患者的免疫监测的标准。
Thirty-five HLA-A2+ patients with completely resected stage I-III melanoma were vaccinated multiple times over 6 months with a modified melanoma peptide, gp100209–2M, emulsified in Montanide adjuvant. Direct ex vivo gp100209–2M tetramer analysis of pre- and postvaccine peripheral blood mononuclear cells (PBMCs) demonstrated significant increases in the frequency of tetramer+ CD8+ T cells after immunization for 33 of 35 evaluable patients (median, 0.36%; range, 0.05–8.9%). Ex vivo IFN-γ cytokine flow cytometry analysis of postvaccine PBMCs after brief gp100209–2M in vitro activation showed that for all of the patients studied tetramer+ CD8+ T cells produced IFN-γ; however, some patients had significant numbers of tetramer+ IFN-γ− CD8+T cells suggesting functional anergy. Additionally, 8 day gp100209–2M in vitro stimulation (IVS) of pre- and postvaccine PBMCs resulted in significant expansion of tetramer+ CD8+ T cells from postvaccine cells for 34 patients, and these IVS tetramer+ CD8+ T cells were functionally responsive by IFN-γ cytokine flow cytometry analysis after restimulation with either native or modified gp100 peptide. However, correlated functional and phenotype analysis of IVS-expanded postvaccine CD8+ T cells demonstrated the proliferation of functionally anergic gp100209–2M- tetramer+ CD8+ T cells in several patients and also indicated interpatient variability of gp100209–2M stimulated T-cell proliferation. Flow cytometry analysis of cryopreserved postvaccine PBMCs from representative patients showed that the majority of tetramer+ CD8+ T cells (78.1 ± 4.2%) had either an “effector” (CD45 RA+/CCR7−) or an “effector-memory” phenotype (CD45RA−/CCR7−). Notably, analysis of PBMCs collected 12–24 months after vaccine therapy demonstrated the durable presence of gp100209–2M-specific memory CD8+ T cells with high proliferation potential. Overall, this report demonstrates that after vaccination with a MHC class I-restricted melanoma peptide, resected nonmetastatic melanoma patients can mount a significant antigen-specific CD8+ T-cell immune response with a functionally intact memory component. The data further support the combined use of tetramer binding and functional assays in correlated ex vivo and IVS settings as a standard for immunomonitoring of cancer vaccine patients.
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影响因子：
20.3
作者：
Rooney, CM;Smith, CA;Heslop, HE
通讯作者：
Heslop, HE
影响因子：
7.3
作者：
Keller CW;Freigang S;Lünemann JD
通讯作者：
Lünemann JD
影响因子：
20.3
作者：
Jie Yang;Victor M. Lemas;Ian W. Flinn;Chris Krone;R. Ambinder
通讯作者：
Jie Yang;Victor M. Lemas;Ian W. Flinn;Chris Krone;R. Ambinder
病毒特异性 CTL 的诱导作为增加表位表达的功能：反应稳定上升，直到达到过高水平的表位。
DOI：
--
发表时间：
1999
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Wherry,EJ;Puorro,KA;Porgador,A;Eisenlohr,LC
通讯作者：
Eisenlohr,LC
快照：效应 T 细胞和记忆 T 细胞分化。
影响因子：
64.5
作者：
Pipkin,MatthewE;Rao,Anjana
通讯作者：
Rao,Anjana