RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers.
RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers.
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DOI：
10.1186/s13046-022-02289-2
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发表时间：
2022-04-23
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对检查点阻断的总体应答率仍然不令人满意，部分原因是免疫抑制性肿瘤微环境。目前临床试验中使用的是一种视黄酸相关孤儿受体γt（RORγt）激动剂（LYC-55716）与抗PD-1联合使用，但Th 17细胞转录因子RORγt如何增强PD-1在肿瘤微环境中的抗肿瘤免疫力仍不清楚。使用qPCR测定分析mRNA的表达。使用流式细胞术对细胞进行分选和分析。使用Transwell测定分析细胞迁移。使用Biacore测定与RORγt蛋白的结合亲和力。使用基于RORγt GAL 4细胞的报告基因测定来测量RORγt驱动的荧光素酶报告基因表达的活性。我们设计了一种有效的选择性小分子RORγt激动剂（8-074），在同基因肿瘤模型中显示出稳健的抗肿瘤疗效，并提高了抗PD-1在小鼠肺癌模型中的疗效。RORγt激动剂治疗增加了肿瘤内CD 8 + T细胞，这与CXCL 10和单核细胞衍生的树突状细胞（MoDC）相关。此外，RORγt激动剂通过上调CCL 20和CCR 6表达促进17型T细胞迁移以及17型T细胞肿瘤浸润。CCL 20诱导MoDC迁移，而衍生自MoDC的CXCL 10促进CD 8 + T细胞迁移。我们的结果表明，RORγt激动剂提高了抗PD-1的疗效。RORγt激动剂增加了MoDC的迁移，这增加了局部CXCL 10的水平，从而促进了CD 8 + T细胞肿瘤浸润。我们的研究结果提供了RORγt激动剂在免疫治疗中的机制见解，并提供了靶向RORγt激动剂以改善癌症中PD-1抗体疗效的策略。在线版本包含补充材料，可通过10.1186/s13046-022-02289-2获得。
The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive. The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression. We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration. Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers. The online version contains supplementary material available at 10.1186/s13046-022-02289-2.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
16.6
作者：
Hirako, Isabella C.;Ataide, Marco A.;Faustino, Lucas;Assis, Patricia A.;Sorensen, Elizabeth W.;Ueta, Hisashi;Araujo, Natalia M.;Menezes, Gustavo B.;Luster, Andrew D.;Gazzinelli, Ricardo T.
通讯作者：
Gazzinelli, Ricardo T.
影响因子：
20.3
作者：
Kryczek, Ilona;Banerjee, Mousumi;Zou, Weiping
通讯作者：
Zou, Weiping