Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, PR China.
Gut. 2023 Apr;72(4):624-637. doi: 10.1136/gutjnl-2021-326581. Epub 2022 Aug 24.
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.
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 SOX9 or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations.
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.
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.
许多癌症利用胚胎基因进行快速生长并逃避免疫系统。SOX9 在许多肿瘤中上调，但 SOX9 在介导免疫抑制肿瘤微环境中的作用尚不清楚。在这里，我们旨在剖析 SOX9 介导的癌症干性特征和免疫抑制微环境在晚期胃腺癌 (GAC) 中的作用，以发现新的治疗方法。
使用批量 RNAseq/scRNA-seq、患者来源的细胞/模型和广泛的功能研究，鉴定 SOX9 及其靶基因在体外和体内的表达和功能。在与肿瘤细胞共培养的 PBMCs 或 CD45 免疫细胞中研究免疫反应，使用 KP-Luc2 同基因模型评估组合的疗效。
SOX9 是 GAC 中上调最明显的 SOX 基因之一，在原发和转移组织中高度表达，并与预后不良相关。在与来自 GAC 患者的 PBMCs/CD45 细胞共培养时，患者来源的 GAC 细胞中 SOX9 的缺失显著降低了癌症干性特征、肿瘤形成和转移，并且一致增加了 CD8 T 细胞反应。RNA 测序确定白血病抑制因子 (LIF) 是肿瘤细胞中受 SOX9 调控的顶级分泌分子，在恶性腹水富集并介导 SOX9 诱导的 M2 巨噬细胞重极化并抑制 T 细胞功能。
上皮 SOX9 通过旁分泌 LIF 因子在 GAC 中对 CD8 T 细胞反应和修饰巨噬细胞功能至关重要。靶向 LIF/LIFR 和 CSF1R 的联合治疗具有靶向 SOX9 介导的癌症干性、T 细胞免疫抑制和转移的巨大潜力，提示针对晚期 GAC 的新型联合治疗。
