Familial adenomatous polyposis (FAP) is a heritable disease that increases the risk of colorectal cancer (CRC) development because of heterozygous mutations in Little is known about the microenvironment of FAP. Here, single-cell RNA sequencing was performed on matched normal tissues, adenomas, and carcinomas from four patients with FAP. We analyzed the transcriptomes of 56,225 unsorted single cells, revealing the heterogeneity of each cell type, and compared gene expression among tissues. Then we compared the gene expression with that of sporadic CRC. Furthermore, we analyzed specimens of 26 FAP patients and 40 sporadic CRC patients by immunohistochemistry. Immunosuppressiveness of myeloid cells, fibroblasts, and regulatory T cells was upregulated even in the early stages of carcinogenesis. CD8 T cells became exhausted only in carcinoma, although the cytotoxicity of CD8 T cells was gradually increased according to the carcinogenic step. When compared with those in the sporadic CRC microenvironment, the composition and function of each cell type in the FAP-derived CRC microenvironment had differences. Our findings indicate that an immunosuppressive microenvironment is constructed from a precancerous stage in FAP.

中文翻译：

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家族性腺瘤性息肉病结直肠癌癌变过程中微环境的变化

家族性腺瘤性息肉病（FAP）是一种遗传性疾病，由于杂合突变会增加结直肠癌（CRC）发展的风险，但对 FAP 的微环境知之甚少。在这里，对四名 FAP 患者的匹配正常组织、腺瘤和癌进行了单细胞 RNA 测序。我们分析了 56,225 个未分选的单细胞的转录组，揭示了每种细胞类型的异质性，并比较了组织之间的基因表达。然后我们将基因表达与散发性结直肠癌的基因表达进行比较。此外，我们通过免疫组织化学分析了 26 名 FAP 患者和 40 名散发性 CRC 患者的标本。即使在癌变的早期阶段，骨髓细胞、成纤维细胞和调节性 T 细胞的免疫抑制也会上调。尽管CD8 T细胞的细胞毒性随着致癌步骤逐渐增加，但CD8 T细胞仅在癌症中耗尽。与散发性CRC微环境中的细胞相比，FAP衍生的CRC微环境中每种细胞类型的组成和功能都存在差异。我们的研究结果表明，免疫抑制微环境是从 FAP 的癌前阶段开始构建的。