Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells.
Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells.
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DOI：
10.1158/2326-6066.cir-17-0134
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发表时间：
2018-03
影响因子：
10.1
通讯作者：
Demaria S
中科院分区：
文献类型：
--
作者：
Rudqvist NP;Pilones KA;Lhuillier C;Wennerberg E;Sidhom JW;Emerson RO;Robins HS;Schneck J;Formenti SC;Demaria S
免疫检查点抑制剂激活T细胞来排斥肿瘤。独特的肿瘤突变是关键的t细胞靶点，但对成功的抗肿瘤t细胞反应的性质缺乏全面的了解。为了研究与治疗成功和失败相关的T细胞受体（TCR）库，我们使用了一种特征明确的小鼠癌，在接受放疗（RT）和抗ctla -4联合治疗（而不是单独治疗）的小鼠中被CD8 T细胞排斥，并通过对TCRB CDR3区域的高通量测序全面分析了肿瘤浸润淋巴细胞（TILs）。联合治疗可提高TIL密度和CD8/CD4比值。对T细胞克隆频率的评估表明，与未治疗的肿瘤相比，抗ctla -4导致更少的克隆和更多的寡克隆库。相比之下，RT增加了CD8/CD4比率并扩大了TCR库，当与抗ctla -4联合使用时，这些选定的T细胞克隆增殖。CDR3序列的分层聚类显示了不同小鼠共享的tcr的治疗特异性聚类。丰富的克隆型在动物之间普遍共享，但治疗特异性。氨基酸序列相似性分析显示，与对照组相比，RT+ anti-CTLA-4治疗的肿瘤中显性CDR3基序的数量和丰富度显著增加。与CD8+ T细胞识别的单一肿瘤抗原反应的tcr库是异质性的，但高度克隆，与治疗无关。总的来说，数据支持一个模型，即实现肿瘤排斥需要不同的TCR库，并且可能是RT和CTLA-4阻断之间协同作用的基础。
Immune checkpoint inhibitors activate T cells to reject tumors. Unique tumor mutations are key T-cell targets, but a comprehensive understanding of the nature of a successful antitumor T-cell response is lacking. To investigate the T-cell receptor (TCR) repertoire associated with treatment success versus failure we used a well-characterized mouse carcinoma that is rejected by CD8 T cells in mice treated with radiotherapy (RT) and anti–CTLA-4 in combination, but not as monotherapy, and comprehensively analyzed tumor-infiltrating lymphocytes (TILs) by high-throughput sequencing of the TCRB CDR3 region. The combined treatment increased TIL density and CD8/CD4 ratio. Assessment of the frequency of T cell clones indicated that anti–CTLA-4 resulted in fewer clones and a more oligoclonal repertoire compared to untreated tumors. In contrast, RT increased the CD8/CD4 ratio and broadened the TCR repertoire, and when used in combination with anti–CTLA-4, these selected T cell clones proliferated. Hierarchical clustering of CDR3 sequences showed a treatment-specific clustering of TCRs that were shared by different mice. Abundant clonotypes were commonly shared between animals and yet treatment-specific. Analysis of amino-acid sequence similarities revealed a significant increase in the number and richness of dominant CDR3 motifs in tumors treated with RT+anti–CTLA-4 compared to control. The repertoire of TCRs reactive with a single tumor antigen recognized by CD8+ T cells was heterogeneous but highly clonal, irrespective of treatment. Overall, data support a model whereby a diverse TCR repertoire is required to achieve tumor rejection and may underlie the synergy between RT and CTLA-4 blockade.