家族性腺瘤性息肉病（FAP）是一种遗传性疾病，其特点是大量结直肠腺瘤的发展，并有很高的风险进展为结直肠肿瘤。腺瘤性息肉病（APC）基因的突变常常是该疾病的起源，也是大部分自发性结直肠肿瘤的起源。因此，APC被认为是一种抑制肿瘤的基因。虽然我们已经充分了解了APC在肠道上皮组织稳态中的作用，但其在免疫反应中的重要性还没有明确定义。我们最近的研究表明，APC蛋白参与了CD4和CD8T细胞反应的各个阶段。这促使我们对携带APC突变的FAP患者进行了一系列免疫细胞特征的调查。我们研究了12例FAP患者和年龄、性别相匹配的健康对照组。我们表征了外周血中的免疫细胞谱系以及免疫细胞在全血或纯化T细胞中对不同刺激的体外反应能力。我们使用了各种实验方法，包括多参数流式细胞术、NanosString基因表达分析、多重和常规ELISA、共聚焦显微镜和基于计算机的图像分析方法。我们发现，几种T细胞和自然杀伤细胞（NK细胞）亚群的百分比、几个与先天或适应性免疫刺激诱导的基因的表达以及多个细胞因子和趋化因子的产生均存在差异。此外，T细胞对趋化因子的迁移能力始终受到影响。最后，FAP细胞毒性T细胞与肿瘤靶细胞之间的免疫突触结构较差。我们这个初步研究的发现表明，FAP患者中多种免疫细胞功能失调以及结肠上皮发育异常可能有助于长期的息肉和结直肠肿瘤的发展。尽管由于这种罕见疾病患者样本数量有限，我们的发现处于初步发现阶段，但这为将免疫细胞异常纳入息肉病理学的考虑提供了新的视角。 2023 Cuche, Mastrogiovanni, Juzans, Laude, Ungeheuer, Krentzel, Gariboldi, Scott-Algara, Madec, Goyard, Floch, Chauveau-Le Friec, Lafaye, Renaudat, Le Bidan, Micallef, Schmutz, Mella, Novault, Hasan, Duffy, Di Bartolo and Alcover版权所有。

Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC is therefore considered a tumor suppressor gene. While the role of APC in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying APC mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond ex vivo to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.Copyright © 2023 Cuche, Mastrogiovanni, Juzans, Laude, Ungeheuer, Krentzel, Gariboldi, Scott-Algara, Madec, Goyard, Floch, Chauveau-Le Friec, Lafaye, Renaudat, Le Bidan, Micallef, Schmutz, Mella, Novault, Hasan, Duffy, Di Bartolo and Alcover.