Kristen E. Pauken, Vikram R. Juneja, P. Sage, M. LaFleur, J. Kuchroo, A. Ringel, N. Ron-Harel, Seth Maleri, G. Freeman, Nicolas Chevrier, M. Haigis, A. Sharpe
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引用次数: 0
Abstract
Although PD-1 pathway inhibitors are revolutionizing cancer treatment, the mechanisms by which PD-1 regulates anti-tumor immunity are not fully understood. Following subcutaneous transplantation of MC38 adenocarcinoma tumor cells into mice, we show that complete loss of PD-1 selectively on CD8+ T cells improved metabolic activity and functions in the tumor microenvironment (TME). Since clinically PD-1 inhibitors likely act on T cells post-priming, we next deleted PD-1 after initial priming and restricted deletion to roughly 50% of cells. Loss of PD-1 led to T cell-intrinsic boosts in metabolism and CD8+ T cells that lost PD-1 after priming preferentially formed anti-tumor memory cells, suggesting PD-1 antagonizes memory formation. Unexpectedly, there was also a bystander effect that improved functions of PD-1 expressing CD8+ T cells in the TME. These data suggest that complete loss of PD-1 is not necessary for optimal tumor immunity, and that enhancing the functions of a subset of CD8+ T cells can promote an antitumor microenvironment and immunologic memory. Citation Format: Kristen E. Pauken, Vikram R. Juneja, Peter T. Sage, Martin W. LaFleur, Juhi R. Kuchroo, Alison Ringel, Noga Ron-Harel, Seth P. Maleri, Gordon J. Freeman, Nicolas Chevrier, Marcia C. Haigis, Arlene H. Sharpe. PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A19.
尽管PD-1途径抑制剂正在彻底改变癌症治疗,但PD-1调节抗肿瘤免疫的机制尚不完全清楚。将MC38腺癌肿瘤细胞皮下移植到小鼠体内后,我们发现CD8+ T细胞上PD-1的选择性完全丧失改善了肿瘤微环境(TME)中的代谢活性和功能。由于临床上PD-1抑制剂可能在T细胞启动后起作用,因此我们在初始启动后删除PD-1,并将删除限制在大约50%的细胞中。PD-1缺失导致T细胞内在代谢增强,启动后缺失PD-1的CD8+ T细胞优先形成抗肿瘤记忆细胞,提示PD-1拮抗记忆形成。出乎意料的是,还存在一种旁观者效应,可以改善TME中表达CD8+ T细胞的PD-1功能。这些数据表明,PD-1的完全丧失并不是最佳肿瘤免疫的必要条件,增强CD8+ T细胞亚群的功能可以促进抗肿瘤微环境和免疫记忆。引文格式:Kristen E. Pauken, Vikram R. Juneja, Peter T. Sage, Martin W. LaFleur, Juhi R. Kuchroo, Alison Ringel, Noga Ron-Harel, Seth P. Maleri, Gordon J. Freeman, Nicolas Chevrier, Marcia C. Haigis, Arlene H. SharpePD-1调节通过改善肿瘤中PD-1+和PD-1- CD8+ T细胞的代谢适合度来促进抗肿瘤免疫[摘要]。摘自:AACR肿瘤免疫学和免疫治疗特别会议论文集;2017年10月1-4日;波士顿,MA。费城(PA): AACR;癌症免疫学杂志,2018;6(9增刊):摘要nr - A19。