TY - JOUR T1 - Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment JF - Gut JO - Gut SP - 624 LP - 637 DO - 10.1136/gutjnl-2021-326581 VL - 72 IS - 4 AU - Yibo Fan AU - Yuan Li AU - Xiaodan Yao AU - Jiangkang Jin AU - Ailing Scott AU - Bovey Liu AU - Shan Wang AU - Longfei Huo AU - Ying Wang AU - Ruiping Wang AU - Melissa Pool Pizzi AU - Lang Ma AU - Shan Shao AU - Matheus Sewastjanow-Silva AU - Rebecca Waters AU - Deyali Chatterjee AU - Bin Liu AU - Namita Shanbhag AU - Guang Peng AU - George Adrian Calin AU - Pawel Karol Mazur AU - Samir M Hanash AU - Jo Ishizawa AU - Yuki Hirata AU - Osamu Nagano AU - Zhenning Wang AU - Linghua Wang AU - Wa Xian AU - Frank McKeon AU - Jaffer A Ajani AU - Shumei Song Y1 - 2023/04/01 UR - http://gut.bmj.com/content/72/4/624.abstract N2 - 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.All data relevant to the study are included in the article or uploaded as supplementary information. Data available on request. ER -