Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion.
Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion.
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DOI：
10.1016/j.immuni.2015.12.018
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发表时间：
2016-01-19
期刊：
影响因子：
32.4
通讯作者：
Wolchok JD
中科院分区：
文献类型：
--
作者：
Malandro N;Budhu S;Kuhn NF;Liu C;Murphy JT;Cortez C;Zhong H;Yang X;Rizzuto G;Altan-Bonnet G;Merghoub T;Wolchok JD
目前的癌症免疫治疗方法旨在利用天然T细胞对肿瘤的反应。一个限制是从免疫库中消除自身抗原特异性T细胞。使用一个系统，其中前体频率可以在小鼠黑色素瘤模型中操作，我们证明了自身肿瘤抗原特异性的CD4+ T细胞的克隆丰度与抗肿瘤疗效呈正相关。在升高的前体频率下，克隆内竞争损害了肿瘤特异性CD4+ T细胞群的初始活化和总体扩增。然而，通过克隆衍生的帮助，这个群体获得了多功能效应表型和抗肿瘤免疫增强。相反，由于不可逆的T细胞耗竭，效应子功能的发展在低前体频率下减弱。我们的研究结果表明，T细胞克隆丰度对表型结果的差异性影响应在过继性T细胞疗法的设计过程中加以考虑，包括使用工程化T细胞。
Current approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrate that the clonal abundance of CD4+ T cells specific for self-tumor antigen positively correlated with antitumor efficacy. At elevated precursor frequencies, intraclonal competition impaired initial activation and overall expansion of the tumor specific CD4+ T cell population. However, through clonally derived help, this population acquired a polyfunctional effector phenotype and antitumor immunity was enhanced. Conversely, development of effector function was attenuated at low precursor frequencies due to irreversible T cell exhaustion. Our findings assert that the differential effects of T cell clonal abundance on phenotypic outcome should be considered during the design of adoptive T cell therapies, including use of engineered T cells.