A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer^1,2,3; however, much less is known about how pre-malignant or early invasive tumours evade immune detection. Here, to understand this process in early colorectal cancers (CRCs), we investigated how naive colon cancer organoids that were engineered in vitro to harbour Apc-null, Kras^G12D and Trp53-null (AKP) mutations adapted to the in vivo native colonic environment. Comprehensive transcriptomic and chromatin analyses revealed that the endoderm-specifying transcription factor SOX17 became strongly upregulated in vivo. Notably, whereas SOX17 loss did not affect AKP organoid propagation in vitro, its loss markedly reduced the ability of AKP tumours to persist in vivo. The small fraction of SOX17-null tumours that grew displayed notable interferon-γ (IFNγ)-producing effector-like CD8⁺ T cell infiltrates in contrast to the immune-suppressive microenvironment in wild-type counterparts. Mechanistically, in both endogenous Apc-null pre-malignant adenomas and transplanted organoid-derived AKP CRCs, SOX17 suppresses the ability of tumour cells to sense and respond to IFNγ, preventing anti-tumour T cell responses. Finally, SOX17 engages a fetal intestinal programme that drives differentiation away from LGR5⁺ tumour cells to produce immune-evasive LGR5⁻ tumour cells with lower expression of major histocompatibility complex class I (MHC-I). We propose that SOX17 is a transcription factor that is engaged during the early steps of colon cancer to orchestrate an immune-evasive programme that permits CRC initiation and progression.

癌症的一个标志是避免免疫破坏。这个过程主要在局部晚期或转移性癌症中进行了研究^1,2,3;然而，关于癌前或早期浸润性肿瘤如何逃避免疫检测，人们知之甚少。在这里，为了了解早期结直肠癌 （CRC） 中的这一过程，我们研究了在体外设计以携带 Apc-null、Kras^G12D 和 Trp53-null （AKP） 突变的幼稚结肠癌类器官如何适应体内天然结肠环境。全面的转录组学和染色质分析显示，内胚层特异性转录因子 SOX17 在体内强烈上调。值得注意的是，虽然 SOX17 缺失不会影响 AKP 类器官在体外的繁殖，但其缺失显着降低了 AKP 肿瘤在体内持续存在的能力。与野生型肿瘤的免疫抑制微环境相比，生长的一小部分 SOX17 缺失肿瘤显示出显着的产生干扰素γ （IFNγ） 效应子样 CD8⁺ T 细胞浸润。从机制上讲，在内源性 Apc 缺失癌前腺瘤和移植的类器官衍生的 AKP CRC 中，SOX17 抑制肿瘤细胞感知和响应 IFNγ 的能力，从而阻止抗肿瘤 T 细胞反应。最后，SOX17 参与胎儿肠道程序，该程序驱使分化离开 LGR5⁺ 肿瘤细胞，以产生免疫逃避的 LGR5⁻ 肿瘤细胞，主要组织相容性复合物 I 类 （MHC-I） 的表达较低。我们提出 SOX17 是一种转录因子，在结肠癌的早期阶段参与，以协调允许 CRC 启动和进展的免疫逃避程序。