T细胞受体
CD8型
剧目
生物
细胞毒性T细胞
T细胞
免疫疗法
肿瘤浸润淋巴细胞
免疫学
抗原
癌症研究
免疫系统
遗传学
声学
物理
体外
作者
Nils Rudqvist,Karsten A. Pilones,Claire Lhuillier,Erik Wennerberg,John-William Sidhom,Ryan Emerson,Harlan Robins,Jonathan P. Schneck,Silvia C. Formenti,Sandra Demaria
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2018-01-31
卷期号:6 (2): 139-150
被引量:167
标识
DOI:10.1158/2326-6066.cir-17-0134
摘要
Abstract 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 TCRΒ 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 with 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 with 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. Cancer Immunol Res; 6(2); 139–50. ©2017 AACR.
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