免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
JAK 抑制对缺乏 IFN-γ通路的黑色素瘤的选择性抑制依赖于 T 细胞和宿主 TNF 信号
英文原题：Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling.
查看英文原题
Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling.
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中文摘要
黑色素瘤患者对免疫检查点阻断剂（ICBs）的治疗耐药是一个紧迫的问题，其中肿瘤丢失IFN-γ信号基因是一个主要的潜在机制。
然而，克服这一耐药机制的策略在很大程度上仍难以实现。此外，鉴于肿瘤浸润T细胞（TILs）在ICBs中不可或缺的作用，关于肿瘤内在的IFN-γ信号缺失（IFNγR1 KO）如何影响TILs，目前知之甚少。
在此，我们报道IFNγR1 KO黑色素瘤的TILs浸润和功能均降低。IFNγR1 KO黑色素瘤具有一个以活化JAK1/2为中心的组成性活跃蛋白酪氨酸激酶网络。在机制上，JAK1/2的活化由增强的mTOR所介导。
重要的是，使用Ruxolitinib抑制JAK1/2可选择性地抑制IFNγR1 KO黑色素瘤的生长，而不抑制对照黑色素瘤，且依赖于T细胞和宿主TNF。
总之，我们的结果揭示了肿瘤内在IFN-γ信号在塑造TILs中的重要作用，并展现了一种靶向治疗策略，可绕过IFN-γ信号缺陷黑色素瘤的ICB耐药。
展开英文摘要原文
Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue, of which tumor loss of IFN-γ signaling genes is a major underlying mechanism.
However, strategies of overcoming this resistance mechanism have been largely elusive.
Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1 KO ) impacts TILs.
Here, we report that IFNγR1 KO melanomas have reduced infiltration and function of TILs. IFNγR1 KO melanomas harbor a network of constitutively active protein tyrosine kinases centered on activated JAK1/2.
Mechanistically, JAK1/2 activation is mediated by augmented mTOR.
Importantly, JAK1/2 inhibition with Ruxolitinib selectively suppresses the growth of IFNγR1 KO but not scrambled control melanomas, depending on T cells and host TNF.
Together, our results reveal an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a targeted therapy to bypass ICB resistance of melanomas defective of IFN-γ signaling.
论文信息
- 作者
- Shen H、Huang F、Zhang X、Ojo OA、Li Y、Trummell HQ、Anderson JC、Fiveash J
- 第一作者单位
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA.United States
- 通讯作者单位
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA. Lewisshi@uabmc.edu.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究 · 美国政府（非公共卫生署）资助研究
- 期刊
- Nature communications2022 Aug 25
- 原文标识
- PubMed 36008408 · DOI 10.1038/s41467-022-32754-7
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