Department of Immunotherapeutics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
MEDINET Co., Ltd 2-3-12 Shin-Yokohama, Kohoku-ku, Yokohama, Kanagawa, 222-0033, Japan.
Sci Rep. 2018 Jan 18;8(1):1058. doi: 10.1038/s41598-018-19548-y.
To facilitate the optimization of cancer immunotherapy lacking immune-related adverse events, we performed TCR repertoire analysis of tumor-infiltrating CD8 T-cells in B16 melanoma-bearing mice receiving anti-PD-1, anti-CTLA-4, anti-4-1BB, anti-CD4 or a combination of anti-PD-1 and 4-1BB antibodies. Although CD8 T-cells in the tumor were activated and expanded to a greater or lesser extent by these therapies, tumor growth suppression was achieved only by anti-PD-1, anti-PD-1/4-1BB combined, or by anti-CD4 treatment, but not by anti-CTLA-4 or anti-4-1BB monotherapy. Increased CD8 T cell effector function and TCR diversity with enrichment of certain TCR clonotypes in the tumor was associated with anti-tumor effects. In contrast, polyclonal activation of T-cells in the periphery was associated with tissue damage. Thus, optimal combination therapy increases TCR diversity with extended activation of selective CD8 T-cells specifically in the tumor but not in the periphery. Incorporation of the concept of evenness for the TCR diversity is proposed.
为了促进缺乏免疫相关不良反应的癌症免疫疗法的优化，我们对接受抗 PD-1、抗 CTLA-4、抗 4-1BB、抗 CD4 或抗 PD-1 和 4-1BB 联合抗体治疗的 B16 黑色素瘤荷瘤小鼠的肿瘤浸润 CD8 T 细胞的 TCR 库进行了分析。尽管这些疗法在不同程度上激活和扩增了肿瘤中的 CD8 T 细胞，但只有抗 PD-1、抗 PD-1/4-1BB 联合或抗 CD4 治疗才能抑制肿瘤生长，而抗 CTLA-4 或抗 4-1BB 单药治疗则不能。肿瘤中 CD8 T 细胞效应功能的增加和 TCR 多样性的增加，以及某些 TCR 克隆型的富集与抗肿瘤作用相关。相比之下，外周 T 细胞的多克隆激活与组织损伤相关。因此，最佳的联合治疗通过选择性地在肿瘤中而不是在外周中延长激活特定的 CD8 T 细胞来增加 TCR 多样性。提出了纳入 TCR 多样性均匀性概念的建议。
