CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
TIL（肿瘤浸润淋巴细胞）中 AKT 的直接激活显著增加干扰素-γ（IFN-γ），从而促使对 PD-1 检查点阻断耐药的肿瘤消退
英文原题：Direct AKT activation in tumor-infiltrating lymphocytes markedly increases interferon-γ (IFN-γ) for the regression of tumors resistant to PD-1 checkpoint blockade.
查看英文原题
Direct AKT activation in tumor-infiltrating lymphocytes markedly increases interferon-γ (IFN-γ) for the regression of tumors resistant to PD-1 checkpoint blockade.
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中文摘要
针对抑制性受体如程序性细胞死亡受体-1（PD-1）的PD-1免疫检查点阻断已彻底改变了癌症治疗。针对肿瘤抗原的有效免疫反应需要肿瘤浸润T细胞（TILs）的浸润和激活。
在此背景下，抗原受体复合物（TCR）与共受体CD28的连接激活了细胞内介质AKT（或PKB，蛋白激酶B）及其下游靶点。PD-1抑制AKT/PKB的激活。鉴于此，我们评估了直接激活AKT是否可能有效激活免疫系统，以限制对PD-1检查点阻断耐药的肿瘤生长。
我们发现，AKT小分子激活剂（SC79）限制了对PD-1免疫治疗反应较差的B16肿瘤和EMT-6同系乳腺癌模型的生长。在B16肿瘤中，直接AKT激活诱导了（i）抑制性调节性（Treg）TILs的减少和（ii）效应CD8+ TILs的增加。SC79体内治疗导致表达干扰素-γ（IFN-γ）的CD4+和CD8+ TILs数量大幅增加。这种对IFN-γ表达的影响区分了有反应与无反应的抗肿瘤反应，并可在体外用人T细胞重现。在CD4+FoxP3+Treg TILs中，AKT诱导的IFN-γ表达伴随着抑制活性的丧失、向CD4+辅助性Th1样TILs的转化以及磷酸化SHP2的显著减少。在CD8+ TILs中，我们观察到PLC-γ磷酸化激活的增加。
此外，转录因子T-bet（Tbx21）的基因缺失阻断了所有亚群上IFN-γ表达的增加，同时消除了SC79对肿瘤生长的治疗益处。
我们的研究表明，AKT激活疗法可在CD4和CD8 TIL上诱导IFN-γ，并伴随瘤内抑制性Treg向CD4+ Th1样T细胞转化以及CD8反应的增强。
展开英文摘要原文
PD-1 immune checkpoint blockade against inhibitory receptors such as receptor programmed cell death-1 (PD-1), has revolutionized cancer treatment. Effective immune reactivity against tumour antigens requires the infiltration and activation of tumour-infiltrating T-cells (TILs).
In this context, ligation of the antigen-receptor complex (TCR) in combination with the co-receptor CD28 activates the intracellular mediator AKT (or PKB, protein kinase B) and its downstream targets. PD-1 inhibits the activation of AKT/PKB. Given this, we assessed whether the direct activation of AKT might be effective in activating the immune system to limit the growth of tumors that are resistant to PD-1 checkpoint blockade.
We found that the small molecule activator of AKT (SC79) limited growth of a B16 tumor and an EMT-6 syngeneic breast tumor model that are poorly responsive to PD-1 immunotherapy. In the case of B16 tumors, direct AKT activation induced (i) a reduction of suppressor regulatory (Treg) TILs and (ii) an increase in effector CD8+ TILs. SC79 in vivo therapy caused a major increase in the numbers of CD4+ and CD8+ TILs to express interferon-γ (IFN-γ).
This effect on IFN-γ expression distinguished responsive from non-responsive anti-tumor responses and could be recapitulated ex vivo with human T-cells. In CD4+FoxP3+Treg TILs, AKT induced IFN-γ expression was accompanied by a loss of suppressor activity, the conversation to CD4 + helper Th1-like TILs and a marked reduction in phospho-SHP2. In CD8+ TILs, we observed an increase in the phospho-activation of PLC-γ.
Further, the genetic deletion of the transcription factor T-bet (Tbx21) blocked the increased IFN-γ expression on all subsets while ablating the therapeutic benefits of SC79 on tumor growth.
Our study shows that AKT activation therapy acts to induce IFN-γ on CD4 and CD8 TILs that is accompanied by the intra-tumoral conversation of suppressive Tregs into CD4 + Th1-like T-cells and augmented CD8 responses.
论文信息
- 作者
- Santinon F、Ezzahra BF、Bachais M、Sarabia Pacis A、Rudd CE
- 第一作者单位
- Département de Médecine, Université de Montréal, Montréal, QC, H3C 3J7, Canada.Canada
- 通讯作者单位
- Département de Médecine, Université de Montréal, Montréal, QC, H3C 3J7, Canada. christopher.e.rudd@umontreal.ca.Canada
- 文献类型
- 非美国政府资助研究
- 期刊
- Scientific reports2022 Nov 2
- 原文标识
- PubMed 36323740 · DOI 10.1038/s41598-022-23016-z
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