Quantifying the efficacy of checkpoint inhibitors on CD8(+) cytotoxic T cells for immunotherapeutic applications via single-cell interaction.
Quantifying the efficacy of checkpoint inhibitors on CD8(+) cytotoxic T cells for immunotherapeutic applications via single-cell interaction.
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DOI：
10.1038/s41419-020-03173-7
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发表时间：
2020-11-13
影响因子：
9
通讯作者：
Konry T
中科院分区：
文献类型：
--
作者：
Sullivan MR;Ugolini GS;Sarkar S;Kang W;Smith EC;Mckenney S;Konry T
PD 1/PDL 1通路的抑制在一些患者的癌症治疗中取得了显著的临床成功。然而，许多人对这种治疗几乎没有反应。为了提高PD 1抑制的疗效，正在探索其他检查点抑制剂作为联合治疗选择。TSR-042和TSR-033分别是抑制PD 1和LAG 3通路的新型抗体，预期用于联合治疗。在这里，我们探索了TSR-042和TSR-033单独和组合在单细胞水平上对细胞相互作用的影响。利用我们的液滴微流控平台，我们使用延时显微镜观察这些抗体对抗原呈递后CD 8 + T细胞中钙通量的影响，以及它们对CD 8 + T细胞对人乳腺癌细胞的细胞毒性潜力的影响。该平台使我们能够比以前应用的体外试验更详细地研究这些治疗之间的相互作用及其对T细胞活性的影响。我们能够观察到的新参数包括对靶细胞杀伤的确切时间、接触时间和CD 8 + T细胞的连续杀伤潜力的影响。我们发现用TSR-033抑制LAG 3导致与树突状细胞接触的CD 8 + T细胞的钙波动显著增加。我们还发现，TSR-042和TSR-033的组合似乎协同增加肿瘤细胞杀伤和单细胞水平。这项研究提供了一种新的基于单细胞的评估这些检查点抑制剂对与CD 8 + T细胞的细胞相互作用的影响。
The inhibition of the PD1/PDL1 pathway has led to remarkable clinical success for cancer treatment in some patients. Many, however, exhibit little to no response to this treatment. To increase the efficacy of PD1 inhibition, additional checkpoint inhibitors are being explored as combination therapy options. TSR-042 and TSR-033 are novel antibodies for the inhibition of the PD1 and LAG3 pathways, respectively, and are intended for combination therapy. Here, we explore the effect on cellular interactions of TSR-042 and TSR-033 alone and in combination at the single-cell level. Utilizing our droplet microfluidic platform, we use time-lapse microscopy to observe the effects of these antibodies on calcium flux in CD8+ T cells upon antigen presentation, as well as their effect on the cytotoxic potential of CD8+ T cells on human breast cancer cells. This platform allowed us to investigate the interactions between these treatments and their impacts on T-cell activity in greater detail than previously applied in vitro tests. The novel parameters we were able to observe included effects on the exact time to target cell killing, contact times, and potential for serial-killing by CD8+ T cells. We found that inhibition of LAG3 with TSR-033 resulted in a significant increase in calcium fluctuations of CD8+ T cells in contact with dendritic cells. We also found that the combination of TSR-042 and TSR-033 appears to synergistically increase tumor cell killing and the single-cell level. This study provides a novel single-cell-based assessment of the impact these checkpoint inhibitors have on cellular interactions with CD8+ T cells.
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影响因子：
4.6
作者：
Konry, Tania;Golberg, Alexander;Yarmush, Martin
通讯作者：
Yarmush, Martin
影响因子：
28.5
作者：
Ma W;Gilligan BM;Yuan J;Li T
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Li T
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16.6
作者：
Dura, Burak;Dougan, Stephanie K.;Voldman, Joel
通讯作者：
Voldman, Joel
影响因子：
5.8
作者：
Maio, Michele;Coukos, George;Ibrahim, Ramy
通讯作者：
Ibrahim, Ramy
影响因子：
8
作者：
Ma W;Chen M;Kaushal S;McElroy M;Zhang Y;Ozkan C;Bouvet M;Kruse C;Grotjahn D;Ichim T;Minev B
通讯作者：
Minev B