Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire.
Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire.
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DOI：
10.1158/0008-5472.can-16-2324
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发表时间：
2017-03-15
期刊：
影响因子：
11.2
通讯作者：
Fong L
中科院分区：
文献类型：
--
作者：
Oh DY;Cham J;Zhang L;Fong G;Kwek SS;Klinger M;Faham M;Fong L
虽然免疫检查点阻断可以在许多癌症患者中引起有效的反应，但它也会产生多种且不可预测的免疫相关不良事件（IRAE）。驱动IRAE的机制通常是未知的。由于CTLA-4阻断导致循环T细胞增殖，我们在本研究中检查了伊匹单抗治疗是否导致组织反应性T细胞的克隆扩增。与没有IRAE的患者相比，伊匹单抗在IRAE患者中诱导T细胞库的更大多样化，而不是将T细胞库缩小到有限数量的克隆。具体而言，伊匹单抗引发了克隆型数量的增加，包括新检测到的克隆和总体T细胞克隆性的下降。在治疗后2周内，IRAE发作前，库的初始扩大发生。IRAE患者表现出更大的CD 4+和CD 8 + T细胞的多样性，但没有显示出相对于没有IRAE患者的调节性T细胞数量的差异。对ipilimumab的PSA应答也与T细胞多样性增加相关。我们的研究结果表明，在检查点阻断后，免疫库的快速多样化对癌症患者既有害又有益。
While immune checkpoint blockade elicits efficacious responses in many cancer patients, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAE are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T cell repertoire in IRAE patients compared to patients without IRAE. Specifically, ipiliumumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T cell numbers relative to patients without IRAE. PSA responses to ipilimumab were also associated with increased T cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for cancer patients.