CTLA-4 blockade enhances the CTL responses to the p53 self-tumor antigen
CTLA-4 blockade enhances the CTL responses to the p53 self-tumor antigen
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DOI：
10.4049/jimmunol.166.6.3908
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发表时间：
2001-03-15
影响因子：
4.4
通讯作者：
Sherman, LA
中科院分区：
文献类型：
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作者：
Hernández, J;Ko, A;Sherman, LA
p53是癌症免疫治疗的一个有吸引力的靶点，因为它在许多不同类型的肿瘤中高比例地过表达。然而，它也在正常组织中表达并在体内充当耐受原。以前，在常规和p53缺陷小鼠中对鼠p53（261-269）表位特异性的所有组成部分的详细检查表明，由于p53的表达，已经报道了对肿瘤抗原的耐受性可以通过体内施用抗CTLA-4 mAb来打破。为了克服耐受性并实现p53特异性CTL的最佳活化，本研究评估了抗CTLA-4 mAb对p53特异性库的作用。发现在抗原刺激时阻断CTLA-4接合诱导对p53的CTL应答的剧烈扩增以及记忆T细胞库的成比例扩增。这种效应依赖于CD 4（+）T细胞辅助的存在，并与辅助功能的增强相关。然而，抗CTLA-4治疗没有增强所得p53特异性CTL群体的亲合力，因此不能逆转耐受性的这一重要后果。
p53 is an attractive target for cancer immunotherapy because it is overexpressed in a high proportion of many different types tumors, However, it is also expressed in normal tissues and acts as a toleragen in vivo, Previously, detailed examination of the repertoire specific for the murine p53(261-269) epitope in conventional and p53-deficient mice demonstrated that because of expression of p53, the CD8(+) T cells that respond to this epitope express low-affinity TCRs, It has been reported that tolerance to tumor Ags Can be broken by in vivo administration of anti-CTLA-4 mAb, With the goal of overriding tolerance and achieving optimal activation of p53-specific CTL, the current study has assessed the effect of anti-CTLA-4 mAb on the p53-specific repertoire. It was found that blockade of CTLA-4 engagement at the time of antigenic stimulation induced a vigorous amplification of the CTL responses to p53 as well as proportionate expansion of the memory T cell pool. This effect was dependent on the presence of CD4(+) T cell help and correlated with an enhancement of helper function. However, anti-CTLA-4 treatment did not enhance the avidity of the resultant p53-specific CTL populations and, therefore, could not reverse this important consequence of tolerance.