小柯机器人

美国麻省理工学院Ömer H. Yilmaz等研究人员合作发现，SOX17可使早期结直肠腺瘤和肿瘤免受免疫侵袭。这一研究成果于2024年2月28日在线发表于《自然》杂志。

研究人员表示，癌症的一个特征是逃避免疫破坏。对这一过程的研究主要集中在局部晚期或转移性癌症；然而，人们对恶性肿瘤前期或早期浸润性肿瘤如何逃避免疫检测却知之甚少。

为了了解早期结直肠癌（CRC）的这一过程，研究人员测试了在体外设计成携带Apc缺失、KrasG12D和Trp53缺失（AKP）突变的初始结肠癌类器官如何适应体内原生结肠环境。全面的转录组和染色质分析表明，内胚层特化转录因子SOX17在体内强烈上调。值得注意的是，虽然SOX17的缺失不会影响AKP类器官在体外的繁殖，但它的缺失却显著降低了AKP肿瘤在体内存活的能力。小部分生长的SOX17缺失肿瘤显示出干扰素-γ（IFNγ）分泌的效应样CD8+ T细胞浸润，这与野生型肿瘤的免疫抑制微环境形成了鲜明对比。

从机理上讲，在内源性Apc缺失的恶性前腺瘤和移植的类器官衍生的AKP CRC中，SOX17都会抑制肿瘤细胞感知IFNγ并对其做出反应的能力，从而阻止抗肿瘤T细胞的反应。最后，SOX17参与了胎儿肠道程序，促使LGR5+肿瘤细胞分化，产生具有免疫侵袭性的LGR5-肿瘤细胞，其主要组织相容性复合体I类（MHC-I）表达较低。研究人员认为，SOX17是一种转录因子，在CRC的早期阶段参与协调免疫侵袭性程序，使CRC得以发生和发展。

附：英文原文

Title: SOX17 enables immune evasion of early colorectal adenomas and cancers

Author: Goto, Norihiro, Westcott, Peter M. K., Goto, Saori, Imada, Shinya, Taylor, Martin S., Eng, George, Braverman, Jonathan, Deshpande, Vikram, Jacks, Tyler, Agudo, Judith, Yilmaz, mer H.

Issue&Volume: 2024-02-28

Abstract: A hallmark of cancer is the avoidance of immune destruction. This process has been primarily investigated in locally advanced or metastatic cancer1,2,3; 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, KrasG12D 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.

DOI: 10.1038/s41586-024-07135-3

Source: https://www.nature.com/articles/s41586-024-07135-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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