上皮细胞的SOX9促进免疫抑制性肿瘤微环境
  • SOX9是晚期胃腺癌(GAC)中上调程度最高的SOX基因,在原发性和转移性组织中高度表达,与不良预后相关;
  • 敲除患者来源GAC细胞中的SOX9,并与GAC患者的PBMCs/CD45+细胞共培养,发现SOX9的缺失显著降低肿瘤的干细胞属性、肿瘤形成和转移,并持续增加CD8+T细胞应答;
  • RNA测序鉴定出白血病抑制因子(LIF)是肿瘤细胞中由SOX9调节的最高分泌分子,在恶性腹水中富集,并介导SOX9诱导的M2巨噬细胞重极化和抑制T细胞功能。
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章台柳
SOX9是一种重要的干细胞转录因子,可通过HMG结构域与DNA结合,介导肿瘤细胞的可塑性。SOX9在多种肿瘤中上调表达,而在肿瘤微环境(TME)中的调控作用还尚不清楚。Gut近期发表的文章,发现上皮细胞的SOX9通过旁分泌LIF因子,抑制CD8+ T细胞反应,并影响巨噬细胞功能。提示我们联合靶向LIF/LIFR和CSF1R或可靶向SOX9介导的肿瘤干细胞、T细胞免疫抑制和转移等,或可成为针对晚期GAC的联合疗法。
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Gut [IF:31.793]

Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment

上皮细胞的SOX9通过促进免疫抑制性肿瘤微环境促进胃腺癌的进展和转移

10.1136/gutjnl-2021-326581

2022-08-24, Article

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Objective: Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries.
Methods: Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations.
Results : SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function.
Conclusion: Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.

First Authors:
Yibo Fan

Correspondence Authors:
Jaffer A Ajani,Shumei Song

All Authors:
Yibo Fan,Yuan Li,Xiaodan Yao,Jiangkang Jin,Ailing Scott,Bovey Liu,Shan Wang,Longfei Huo,Ying Wang,Ruiping Wang,Melissa Pool Pizzi,Lang Ma,Shan Shao,Matheus Sewastjanow-Silva,Rebecca Waters,Deyali Chatterjee,Bin Liu,Namita Shanbhag,Guang Peng,George Adrian Calin,Pawel Karol Mazur,Samir M Hanash,Jo Ishizawa,Yuki Hirata,Osamu Nagano,Zhenning Wang,Linghua Wang,Wa Xian,Frank McKeon,Jaffer A Ajani,Shumei Song

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