SOX2 promotes resistance of melanoma with PD-L1 high expression to T-cell-mediated cytotoxicity that can be reversed by SAHA.
SOX2 promotes resistance of melanoma with PD-L1 high expression to T-cell-mediated cytotoxicity that can be reversed by SAHA.
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SOX2 促进 PD-L1 高表达的黑色素瘤对 T 细胞介导的细胞毒性的抵抗，而 SAHA 可逆转这种毒性
DOI：
10.1136/jitc-2020-001037
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发表时间：
2020-11
影响因子：
10.9
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Wu R;Wang C;Li Z;Xiao J;Li C;Wang X;Kong P;Cao J;Huang F;Li Z;Huang Y;Chen Y;Li X;Yang D;Zhang H;Mai J;Feng G;Deng R;Zhu X
背景免疫检查点抑制剂（ICI）在程序性细胞死亡1配体1（PD-L1）高表达的黑色素瘤中诱导更好的肿瘤消退，但失败反应激增。在这项研究中，我们的目的是探索可能解释ICI耐药的其他机制和干预策略，以克服PD-L1高表达的黑色素瘤的耐药性。方法采用移植性黑色素瘤模型和细胞毒实验研究SOX 2在抗肿瘤免疫中的作用。用Western印迹、定量PCR和荧光素酶分析检测JAK-STAT通路的活性。采用表观遗传化合物文库筛选法筛选能够降低SOX 2水平的抑制剂。组蛋白去乙酰化酶抑制剂SAHA单独或与免疫疗法组合在抗肿瘤免疫中的作用也在体外和体内测定。使用从Gene Expression Omnibus和The Cancer Genome Atlas库下载的转录谱和临床数据分析SOX 2的预后影响。结果我们发现SOX 2在减弱黑色素瘤细胞对CD 8 + T细胞杀伤的敏感性中的作用。在机制上，SOX 2抑制细胞因子信号传导的磷酸酶抑制因子3（SOCS 3）和蛋白酪氨酸磷酸酶非受体1型（PTPN 1）转录，诱导JAK-STAT途径的持续激活，从而过表达干扰素刺激的基因抗性标记（ISG.RS）。通过靶向SOX 2-JAK-STAT信号通路，SAHA在体外和体内促进IFNγ或抗PD-1的抗肿瘤功效。此外，SOX 2是PD-L1高表达黑色素瘤患者生存率差和抗PD-1治疗耐药的独立预后因素。结论SOX 2通过抑制JAK-STAT通路和ISG.RS表达，具有免疫逃避CD 8 + T细胞杀伤的功能。我们还提供了在临床上探索ICI与SAHA的新型组合的基本原理，特别是在PD-L1和SOX 2高表达的黑色素瘤中。
Background Immune checkpoint inhibitors (ICIs) induce better tumor regression in melanoma with programmed cell death 1 ligand 1 (PD-L1) high expression, but there has been an upsurge of failed responses. In this study, we aimed to explore the additional mechanisms possibly accounting for ICIs resistance and interventional strategies to overcome the resistance in melanoma with PD-L1 high expression. Methods Melanoma xenografts and cytotoxicity assays were used to investigate function of SOX2 in regulating antitumor immunity. The activity of the janus kinase-signal transducer and activator of transcriptions (JAK-STAT) pathway was investigated by western blots, quantitative PCR and luciferase assay. Epigenetic compounds library screen was employed to identify inhibitors that could decrease SOX2 level. The effect of histone deacetylase inhibitor SAHA in antitumor immunity alone or in combination with immunotherapy was also determined in vitro and in vivo. Prognostic impact of SOX2 was analyzed using transcriptional profiles and clinical data download from the Gene Expression Omnibus and The Cancer Genome Atlas repository. Results We uncovered a role of SOX2 in attenuating the sensitivity of melanoma cells to CD8+ T-cell killing. Mechanistically, SOX2 inhibited phosphatases suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase non-receptor type 1 (PTPN1) transcription, induced duration activation of the JAK-STAT pathway and thereby overexpression of interferon stimulated genes resistance signature (ISG.RS). By targeting the SOX2-JAK-STAT signaling, SAHA promoted the antitumor efficacy of IFNγ or anti-PD-1 in vitro and in vivo. Moreover, SOX2 was an independent prognostic factor for poor survival and resistant to anti-PD-1 therapy in melanoma with PD-L1 high expression. Conclusions Our data unveiled an additional function of SOX2 causing immune evasion of CD8+ T-cell killing through alleviating the JAK-STAT pathway and ISG.RS expression. We also provided a rationale to explore a novel combination of ICIs with SAHA clinically, especially in melanoma with PD-L1 and SOX2 high expression.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
28.2
作者：
Peng W;Chen JQ;Liu C;Malu S;Creasy C;Tetzlaff MT;Xu C;McKenzie JA;Zhang C;Liang X;Williams LJ;Deng W;Chen G;Mbofung R;Lazar AJ;Torres-Cabala CA;Cooper ZA;Chen PL;Tieu TN;Spranger S;Yu X;Bernatchez C;Forget MA;Haymaker C;Amaria R;McQuade JL;Glitza IC;Cascone T;Li HS;Kwong LN;Heffernan TP;Hu J;Bassett RL Jr;Bosenberg MW;Woodman SE;Overwijk WW;Lizée G;Roszik J;Gajewski TF;Wargo JA;Gershenwald JE;Radvanyi L;Davies MA;Hwu P
通讯作者：
Hwu P
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
3.6
作者：
Laga AC;Zhan Q;Weishaupt C;Ma J;Frank MH;Murphy GF
通讯作者：
Murphy GF