SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.
SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.
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DOI：
10.1371/journal.pone.0042459
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shirwan H
中科院分区：
文献类型：
--
作者：
Madireddi S;Schabowsky RH;Srivastava AK;Sharma RK;Yolcu ES;Shirwan H
肿瘤将常规的CD 4 + T细胞转化为诱导的CD 4 + CD 25 + FoxP 3 + T调节（iTreg）细胞，其充当免疫逃避的有效手段。因此，阻断常规CD 4 + T细胞转化为iTreg细胞代表了用于改善各种免疫疗法的功效的有吸引力的靶标。使用一种新形式的4-1BBL分子SA-4-1BBL，我们先前证明了通过4-1BB受体的共刺激使得CD 4+和CD 8 + T效应细胞（Teff）对Treg细胞的抑制难以抵抗，并且增加了与各种临床前肿瘤模型中的治疗功效相关的肿瘤内Teff/Treg细胞比率。在这些研究的基础上，我们在本文中首次表明，据我们所知，通过4-1BB的信号传导通过刺激CD 4 + FoxP 3 − T细胞产生IFN-γ来抑制抗原和TGF-β驱动的幼稚CD 4 + FoxP 3 − T细胞向iTreg细胞的转化。重要的是，SA-4-1BBL治疗阻断了EG.7肿瘤将CD 4 + FoxP 3 − T细胞转化为Treg细胞。结合我们之前的研究，这些结果表明，4-1BB信号通过两种不同的机制对Treg细胞进行负调节：i）抑制CD 4 + FoxP 3 − T细胞转化为iTreg细胞; ii）赋予Treg细胞难以抑制的Teff细胞。鉴于Treg细胞在肿瘤免疫逃避机制中的主导作用，4-1BB信号传导代表了有利地使Teff：Treg平衡向Teff细胞倾斜的有吸引力的靶标，这对癌症免疫治疗具有重要意义。
Tumors convert conventional CD4+ T cells into induced CD4+CD25+FoxP3+ T regulatory (iTreg) cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4+ T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4+and CD8+ T effector (Teff) cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our knowledge, that signaling through 4-1BB inhibits antigen- and TGF-β-driven conversion of naïve CD4+FoxP3− T cells into iTreg cells via stimulation of IFN-γ production by CD4+FoxP3− T cells. Importantly, treatment with SA-4-1BBL blocked the conversion of CD4+FoxP3− T cells into Treg cells by EG.7 tumors. Taken together with our previous studies, these results show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i) inhibiting the conversion of CD4+FoxP3− T cells into iTreg cells and ii) endowing Teff cells refractory to inhibition by Treg cells. Given the dominant role of Treg cells in tumor immune evasion mechanisms, 4-1BB signaling represents an attractive target for favorably tipping the Teff:Treg balance toward Teff cells with important implications for cancer immunotherapy.
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OX40触发调节性T细胞抑制块并促进肿瘤排斥。
影响因子：
15.3
作者：
Piconese, Silvia;Valzasina, Barbara;Colombo, Mario P.
通讯作者：
Colombo, Mario P.
影响因子：
5.5
作者：
Sharma, Rajesh K.;Srivastava, Abhishek K.;Yolcu, Esma S.;MacLeod, Kathryn J.;Schabowsky, Rich-Henry;Madireddi, Shravan;Shirwan, Haval
通讯作者：
Shirwan, Haval
DOI：
10.4049/jimmunol.0803241
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lee SW;Salek-Ardakani S;Mittler RS;Croft M
通讯作者：
Croft M
影响因子：
4.4
作者：
Kwon, BS;Hurtado, JC;Vinay, DS
通讯作者：
Vinay, DS
影响因子：
20.3
作者：
Valzasina, B;Guiducci, C;Colombo, MP
通讯作者：
Colombo, MP