Elevated tumor-associated antigen expression suppresses variant peptide vaccine responses.
Elevated tumor-associated antigen expression suppresses variant peptide vaccine responses.
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DOI：
10.4049/jimmunol.1101555
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发表时间：
2011-11-01
期刊：
影响因子：
--
通讯作者：
Slansky JE
中科院分区：
文献类型：
--
作者：
Kemmler CB;Clambey ET;Kedl RM;Slansky JE
变体肽疫苗在临床上用于扩增与肿瘤相关抗原（TAA）交叉反应的T细胞。为了研究内源性TAA表达升高对变体肽诱导的应答的影响，我们使用GP 70 TAA模型。尽管年轻的BALB/c小鼠显示出对TAA GP 70423 -431（AH 1）的T细胞耐受性，但GP 70的表达和AH 1特异性应答的抑制随着年龄的增长而增加。我们假设，随着TAA表达的增加，变体肽引起的T细胞应答的AH 1交叉反应性降低。控制免疫衰老，我们发现，GP 70表达升高抑制AH 1交叉反应引起的两个AH 1肽变体。一种在年轻小鼠中几乎只引起AH 1交叉反应性T细胞的变体在具有抗体可检测的GP 70表达的老龄小鼠中引起很少或没有T细胞。相比之下，在年轻小鼠中引起较少AH 1交叉反应性T细胞应答的变体在所有测试的老龄小鼠中成功地扩增了AH 1交叉反应性T细胞。然而，这些T细胞以相对短的半衰期结合AH 1/MHC复合物，并且对AH 1肽的离体刺激反应较差。当AH 1肽在疫苗接种前耐受性地给予年幼小鼠时，变体肽疫苗应答也被抑制。对抗体可检测到GP 70表达的未处理小鼠的变体特异性前体T细胞的分析确定，这些T细胞表达PD-1并下调IL-7 R α表达，表明它们是无反应性的或正在缺失。虽然变体肽疫苗随着TAA表达的增加而不太有效，但本文提供的数据也表明互补免疫疗法可以诱导具有功能性TAA识别的T细胞的扩增。
Variant peptide vaccines are used clinically to expand T cells that cross-react with tumor-associated antigens (TAA). To investigate the effects of elevated endogenous TAA expression on variant peptide-induced responses, we used the GP70 TAA model. Although young BALB/c mice display T cell tolerance to the TAA GP70423–431 (AH1), expression of GP70 and suppression of AH1-specific responses increases with age. We hypothesized that as TAA expression increases, the AH1-crossreactivity of variant peptide-elicited T cell responses diminishes. Controlling for immunosenescence, we showed that elevated GP70 expression suppressed AH1-crossreactive responses elicited by two AH1 peptide variants. A variant that elicited almost exclusively AH1-crossreactive T cells in young mice elicited few or no T cells in aging mice with antibody-detectable GP70 expression. In contrast, a variant that elicited a less AH1-crossreactive T cell response in young mice successfully expanded AH1-crossreactive T cells in all aging mice tested. However, these T cells bound the AH1/MHC complex with a relatively short half-life and responded poorly to ex vivo stimulation with the AH1 peptide. Variant peptide vaccine responses were also suppressed when AH1 peptide is administered tolerogenically to young mice prior to vaccination. Analyses of variant-specific precursor T cells from naïve mice with antibody-detectable GP70 expression determined that these T cells expressed PD-1 and had downregulated IL-7Rα expression, suggesting they were anergic or undergoing deletion. Although variant peptide vaccines were less effective as TAA expression increases, data presented here also suggest that complementary immunotherapies may induce the expansion of T cells with functional TAA recognition.
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DOI：
10.1084/jem.20042167
发表时间：
2005-05-16
期刊：
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影响因子：
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