Tumor-induced suppression of CTL expansion and subjugation by gp96-Ig vaccination.
Tumor-induced suppression of CTL expansion and subjugation by gp96-Ig vaccination.
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DOI：
10.1158/0008-5472.can-08-3706
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Podack ER
中科院分区：
文献类型：
--
作者：
Schreiber TH;Deyev VV;Rosenblatt JD;Podack ER
已建立的肿瘤抑制抗肿瘤免疫反应并诱导耐受的机制尚未完全确定，这一现象是肿瘤免疫治疗的重要障碍。单次接种表达gp96-Ig的肿瘤细胞可刺激肿瘤naïve小鼠中肿瘤特异性ctl的扩增，这种扩增被已建立的肿瘤抑制。有趣的是，频繁的疫苗接种可以恢复已有肿瘤的抗肿瘤免疫反应。同基因EG7荷瘤小鼠对频繁接种EG7-gp96- ig具有异质性应答，32%完全应答，68%部分应答。反应者与无反应者的比较显示，外周血中肿瘤特异性CTL扩增与肿瘤大小呈负相关。为了鉴定与有效抗肿瘤免疫应答相关的免疫细胞和分子，使用从接种部位分离的细胞进行RT-PCR阵列。elisa、细胞表型和肿瘤免疫组化也对疫苗应答者和无应答者进行了比较。这些数据表明，T-bet、RORγt、IFNγ、CCL8、CXCL9和CXCL10在接种部位的上调与疫苗诱导的抗肿瘤免疫有关。这些数据与应答者外周血中CTL扩增增加、CD8+细胞和IL-17+细胞对应答性肿瘤的浸润增加以及CD11b+Gr-1+细胞和FoxP3+细胞对应答性肿瘤的浸润减少有关。此外，血清elisa显示，与应答者相比，无应答者的TGF-β显著升高。有趣的是，从应答者和非应答者中分离的CD8+ T细胞在体外具有相同的细胞毒性活性。综上所述，我们的数据表明，已建立的肿瘤可能通过阻止肿瘤特异性CTL的克隆扩增而不诱导能量来逃避免疫监视。
Established tumors suppress anti-tumor immune responses and induce tolerance by incompletely characterized mechanisms, and this phenomenon is an important barrier to tumor immunotherapy. Single vaccination with tumor cells expressing gp96-Ig stimulates robust expansion of tumor-specific CTLs in tumor naïve mice and this expansion is inhibited by established tumors. Interestingly, frequent vaccinations restore anti-tumor immune responses in the presence of established tumors. Syngeneic EG7 tumor bearing mice have heterogeneous responses to frequent vaccination with EG7-gp96-Ig, with 32% complete responders and 68% partial responders. Comparison of responders to non-responders revealed an inverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective anti-tumor immune responses, RT-PCR arrays were performed using cells isolated from the vaccination site. ELISAs, cellular phenotyping and tumor immunohistochemistry were also performed comparing vaccine responders to non-responders. These data demonstrate that upregulation of T-bet, RORγt, IFNγ, CCL8, CXCL9 and CXCL10 at the vaccination site are associated with vaccine-induced anti-tumor immunity. These data correlate with increased CTL expansion in the peripheral blood of responders, increased infiltration of responder tumors by CD8+ cells and IL-17+ cells and decreased infiltration of responder tumors by CD11b+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of TGF-β in non-responders as compared to responders. Interestingly, CD8+ T cells isolated from responders and non-responders have equivalent cytotoxic activity in vitro. Taken together, our data suggest that established tumors may escape immunosurveillance by preventing clonal expansion of tumor specific CTL without inducing anergy.