CTLA4 blockade broadens the peripheral T-cell receptor repertoire.
CTLA4 blockade broadens the peripheral T-cell receptor repertoire.
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DOI：
10.1158/1078-0432.ccr-13-2648
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Ribas A
中科院分区：
文献类型：
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作者：
Robert L;Tsoi J;Wang X;Emerson R;Homet B;Chodon T;Mok S;Huang RR;Cochran AJ;Comin-Anduix B;Koya RC;Graeber TG;Robins H;Ribas A
评价曲美木单抗阻断CTLA-4对外周血单核细胞（PBMC）的免疫调节作用。我们使用下一代测序研究了21例患者PBMC中重排T细胞受体（TCR）可变β（V-β）的互补决定区3（CDR 3），基线和接受曲美木单抗后30-60天。在接受曲美木单抗后，21名患者中有19名患者的TCR V-β CDR 3的独特生产序列中位值增加了30%，21名患者中仅2名患者中位值减少了30%。这些变化是显着的丰富度（p=0.01）和香农指数多样性（p=0.04）。相比之下，从四个健康供体连续收集的PBMC在一年内未显示TCR V-β CDR 3多样性的显著变化。与没有毒性的患者相比，经历曲美木单抗毒性的患者之间的总独特生产性TCR V-β CDR 3序列存在显著差异（p=0.05）。临床应答者和非应答者之间未观察到相关差异。用曲美木单抗阻断CTLA 4使外周T细胞库多样化，代表这类抗体如何调节人免疫系统的药效学作用。
To evaluate the immunomodulatory effects of CTLA-4 blockade with tremelimumab in peripheral blood mononuclear cells (PBMC). We used next generation sequencing to study the complementarity determining region 3 (CDR3) from the rearranged T cell receptor (TCR) variable beta (V-beta) in PBMC of 21 patients, at baseline and 30–60 days after receiving tremelimumab. After receiving tremelimumab there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (p=0.01) and for Shannon index diversity (p=0.04). In comparison, serially collected PBMC from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over one year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared to patients without toxicity (p=0.05). No relevant differences were noted between clinical responders and non-responders. CTLA4 blockade with tremelimumab diversifies the peripheral T cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system.