Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients.
Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients.
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DOI：
10.1126/scitranslmed.3008211
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发表时间：
2014-05-28
影响因子：
17.1
通讯作者：
Fong L
中科院分区：
文献类型：
--
作者：
Cha E;Klinger M;Hou Y;Cummings C;Ribas A;Faham M;Fong L
细胞毒性T淋巴细胞相关抗原-4(CTLA-4)阻断可促进抗肿瘤T细胞免疫和临床应答。抗CTLA-4抗体诱导抗肿瘤反应的机制存在争议。为了确定CTLA-4阻断对T细胞谱系的影响，我们使用下一代深度测序来测量单个重排的T细胞受体β(TCRβ)基因的频率，从而表征重排的多样性，即T细胞克隆型。在转移性去势抵抗前列腺癌和转移性黑色素瘤患者中，CTLA-4的阻断导致T细胞克隆型的扩张和丢失，这与T细胞库的全球更替一致。总体而言，这种处理增加了TCR的多样性，这反映在独特的TCR克隆类型的数量上。在随后的几个月的治疗中，克隆型的保留范围继续演变。虽然随着治疗而增加的克隆类型的数量与临床结果无关，但总体存活率的提高与维持在基线水平的高频克隆有关。相比之下，在总体存活时间较短的患者中，最高频率的克隆型随着治疗的进行而下降。稳定保持的克隆型包括具有高亲和力TCR的T细胞，如病毒反应性T细胞。综上所述，这些结果表明，CTLA-4阻断可诱导T细胞谱系的进化和多样化。此外，临床结果的改善与较少的克隆型丢失有关，这与治疗期间维持高频TCR克隆型是一致的。这些克隆可能代表了先前存在的高亲和力T细胞的存在，这可能与抗肿瘤反应有关。
Cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) blockade can promote antitumor T cell immunity and clinical responses. The mechanism by which anti–CTLA-4 antibodies induces antitumor responses is controversial. To determine the effects of CTLA-4 blockade on the T cell repertoire, we used next-generation deep sequencing to measure the frequency of individual rearranged T cell receptor β (TCRβ) genes, thereby characterizing the diversity of rearrangements, known as T cell clonotypes. CTLA-4 blockade in patients with metastatic castration-resistant prostate cancer and metastatic melanoma resulted in both expansion and loss of T cell clonotypes, consistent with a global turnover of the T cell repertoire. Overall, this treatment increased TCR diversity as reflected in the number of unique TCR clonotypes. The repertoire of clonotypes continued to evolve over subsequent months of treatment. Whereas the number of clonotypes that increased with treatment was not associated with clinical outcome, improved overall survival was associated with maintenance of high-frequency clones at baseline. In contrast, the highest-frequency clonotypes fell with treatment in patients with short overall survival. Stably maintained clonotypes included T cells having high-avidity TCR such as virus-reactive T cells. Together, these results suggest that CTLA-4 blockade induces T cell repertoire evolution and diversification. Moreover, improved clinical outcomes are associated with less clonotype loss, consistent with the maintenance of high-frequency TCR clonotypes during treatment. These clones may represent the presence of preexisting high-avidity T cells that may be relevant in the antitumor response.