PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer.
PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer.
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PRMT5 抑制促进肺癌中 PD-L1 的表达和免疫抵抗
DOI：
10.3389/fimmu.2021.722188
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zheng Y
中科院分区：
文献类型：
--
作者：
Hu R;Zhou B;Chen Z;Chen S;Chen N;Shen L;Xiao H;Zheng Y
蛋白精氨酸转移酶5（PRMT 5）被认为是肿瘤发生的重要调节因子，因为它促进肿瘤细胞增殖、侵袭和转移。研究主要集中在PRMT 5调节肿瘤的内在变化;然而，PRMT 5对肿瘤微环境，特别是免疫细胞的影响在很大程度上是未知的。在这里，我们发现通过遗传或药理学抑制靶向PRMT 5可以减少免疫功能低下小鼠的肺肿瘤进展;然而，这种作用在免疫功能正常的小鼠中减弱。PRMT 5抑制不仅降低了肿瘤细胞的存活率，而且在体外和体内增加了肿瘤细胞CD 274的表达，这激活了PD 1/PD-L1轴并消除了CD 8 +T细胞的抗肿瘤免疫。在机制上，PRMT 5通过组蛋白H4 R3的对称二甲基化、增加H3 R4 me 2s在CD 274启动子位点上的沉积以及抑制CD 274基因表达来调节CD 274基因表达。靶向PRMT 5降低了这种抑制作用，并促进了肺癌中CD 274的表达。然而，PRMT 5抑制剂代表了一把双刃剑，因为它们可以选择性地杀死癌细胞，但也可能破坏抗肿瘤免疫应答。PRMT 5抑制和抗PD-L1治疗的组合导致肿瘤浸润性T细胞的数量增加并增强其功能。我们的研究结果解决了未满足的临床需求，其中PRMT 5抑制与抗PD-L1治疗的组合可能是肺癌治疗的有希望的策略。
Protein arginine transferase 5 (PRMT5) has been implicated as an important modulator of tumorigenesis as it promotes tumor cell proliferation, invasion, and metastasis. Studies have largely focused on PRMT5 regulating intrinsic changes in tumors; however, the effects of PRMT5 on the tumor microenvironment and particularly immune cells are largely unknown. Here we found that targeting PRMT5 by genetic or pharmacological inhibition reduced lung tumor progression in immunocompromised mice; however, the effects were weakened in immunocompetent mice. PRMT5 inhibition not only decreased tumor cell survival but also increased the tumor cell expression of CD274 in vitro and in vivo, which activated the PD1/PD-L1 axis and eliminated CD8+T cell antitumor immunity. Mechanistically, PRMT5 regulated CD274 gene expression through symmetric dimethylation of histone H4R3, increased deposition of H3R4me2s on CD274 promoter loci, and inhibition of CD274 gene expression. Targeting PRMT5 reduced this inhibitory effect and promoted CD274 expression in lung cancer. However, PRMT5 inhibitors represent a double-edged sword as they may selectively kill cancer cells but may also disrupt the antitumor immune response. The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment.
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影响因子：
8.8
作者：
Chiang K;Zielinska AE;Shaaban AM;Sanchez-Bailon MP;Jarrold J;Clarke TL;Zhang J;Francis A;Jones LJ;Smith S;Barbash O;Guccione E;Farnie G;Smalley MJ;Davies CC
通讯作者：
Davies CC
PHD Finger Protein 1 (PHF1) 是组蛋白 H4R3 对称二甲基化的新型读取器，并与 PRMT5-WDR77/CRL4B 复合物协调促进肿瘤发生
影响因子：
14.9
作者：
Liu R;Gao J;Yang Y;Qiu R;Zheng Y;Huang W;Zeng Y;Hou Y;Wang S;Leng S;Feng D;Yu W;Sun G;Shi H;Teng X;Wang Y
通讯作者：
Wang Y
影响因子：
15.9
作者：
Webb, Lindsay M.;Sengupta, Shouvonik;Guerau-de-Arellano, Mireia
通讯作者：
Guerau-de-Arellano, Mireia
影响因子：
14.9
作者：
Liu, Fan;Xu, Ye;Nimer, Stephen D.
通讯作者：
Nimer, Stephen D.
影响因子：
7.3
作者：
Nagai, Yasuhiro;Ji, Mei Q.;Greene, Mark I.
通讯作者：
Greene, Mark I.