Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.
Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.
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DOI：
10.1186/s40425-018-0371-5
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发表时间：
2018-06-11
影响因子：
10.9
通讯作者：
Gilbert MR
中科院分区：
文献类型：
--
作者：
Giles AJ;Hutchinson MND;Sonnemann HM;Jung J;Fecci PE;Ratnam NM;Zhang W;Song H;Bailey R;Davis D;Reid CM;Park DM;Gilbert MR
皮质类固醇通常用于减轻颅内病变患者的浮肿，是对抗免疫相关不良事件(IrAEs)的一线药物，这些不良事件发生在免疫检查点阻断治疗中。然而，目前尚不清楚是否或何时可以在不取消免疫治疗努力的情况下使用皮质类固醇。本研究的目的是评估地塞米松在检查点封锁期间对淋巴细胞活化和增殖的影响，为在免疫治疗作为癌症治疗的同时使用皮质类固醇提供指导。在地塞米松暴露期间，评估淋巴细胞的增殖、分化和细胞因子的产生。人T细胞通过CD3连接刺激，并通过CD28连接或提供CD80(CD28和CTLA-4的共同配体)共同刺激。CTLA-4信号被抗体阻断后被ipilimumab抑制，该药已被批准用于治疗几种实体瘤。采用GL261同基因小鼠颅内模型评价地塞米松在检查点封锁过程中的体内效应，并用流式细胞仪分析免疫细胞群。地塞米松上调CD4和CD8T细胞CTLA-4mRNA和蛋白表达，阻断CD28介导的细胞周期进入和分化。幼稚T细胞最敏感，导致分化程度较高的亚群减少。对地塞米松的抵抗是通过阻断CTLA-4或在地塞米松暴露之前提供强烈的CD28共刺激来实现的。阻断CTLA-4可增加地塞米松刺激的人外周血T细胞干扰素γ的表达，但不增加IL-2的表达。最后，我们发现CTLA-4阻断部分挽救了荷脑胶质瘤小鼠的T细胞数量。阻断CTLA-4与增加干扰素γ产生的肿瘤浸润性T细胞和延长地塞米松治疗的小鼠的生存期有关。地塞米松介导的T细胞抑制通过减弱CD28共刺激途径来减少初始T细胞的增殖和分化。然而，CTLA-4，而不是PD-1阻断可以部分阻止地塞米松对免疫反应的一些抑制作用。本文的在线版本(10.1186/s40425-0180371-5)包含补充材料，可供授权用户使用。
Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment. Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry. Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice. Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response. The online version of this article (10.1186/s40425-018-0371-5) contains supplementary material, which is available to authorized users.
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影响因子：
3.9
作者：
Hinrichs, CS;Palmer, DC;Restifio, NP
通讯作者：
Restifio, NP
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
4.1
作者：
JELSMAN, R;BUCY, PC
通讯作者：
BUCY, PC
影响因子：
10.1
作者：
Hodi FS;Lawrence D;Lezcano C;Wu X;Zhou J;Sasada T;Zeng W;Giobbie-Hurder A;Atkins MB;Ibrahim N;Friedlander P;Flaherty KT;Murphy GF;Rodig S;Velazquez EF;Mihm MC Jr;Russell S;DiPiro PJ;Yap JT;Ramaiya N;Van den Abbeele AD;Gargano M;McDermott D
通讯作者：
McDermott D
影响因子：
7.2
作者：
Berghoff, Anna S.;Fuchs, Elisabeth;Preusser, Matthias
通讯作者：
Preusser, Matthias