整合素β7通过下调IL-17A表达抑制结直肠癌发生发展的机制研究

Colorectal cancer is one of the gastrointestinal malignancies with high incidence and high mortality. Immune system plays a key role in the development and progression of colorectal cancer. Integrin β7 mediates immune cells trafficking to gut-associated lymphoid tissue, which is essential for the homeostasis of gut immunity. The function and underlying mechanism of integrin β7 in colorectal cancer development and progression remain unclear. Using two mouse models of colorectal cancer, we found that integrin β7-deficient mice were more susceptible to colitis-associated colorectal cancer and sporadic colorectal cancer compared with wild-type mice. Moreover, interleukin-17A (IL-17A) was significantly upregulated in β7-deficient mouse tumor. In this project, we will investigate: 1) whether integrin β7 function through regulating IL-17A expression; 2) the cell origin of IL-17A in tumor; 3) the molecular basis of the upregulation of IL-17A expression by integrin β7 deletion in tumor; 4) the relativity between integrin β7 and IL-17A expression in human colorectal cancer tissue and the relationship between integrin β7, IL-17A expression and tumor progression. In general, our study will reveal the function and mechanism of integrin β7 in inhibiting colorectal cancer development and progression, which might provide the theoretical basis for the disease therapy and the novel drug development.

结直肠癌是高发病率、高致死率的消化道恶性肿瘤之一，严重威胁人类健康。免疫在癌症发生发展中发挥关键作用，整合素β7能够介导淋巴细胞向肠道相关淋巴组织处的迁移，对于肠道免疫至关重要，但整合素β7在结直肠癌发生发展中的功能和作用机制尚不明确。我们发现整合素β7缺失小鼠对炎症相关性结直肠癌和散发性结直肠癌的诱导均较为敏感，并且整合素β7缺失小鼠肠道肿瘤组织中IL-17A的表达水平显著提高。本课题将1）探讨整合素β7是否通过调控IL-17A表达发挥功能；2）鉴定整合素β7缺失小鼠肠道肿瘤组织IL-17A的细胞来源；3）研究整合素β7缺失导致肠道组织IL-17A表达上调的分子机制；4）探究整合素β7、IL-17A在结直肠癌组织样本中的表达相关性以及与临床病理特征的关系。本课题将揭示整合素β7通过下调IL-17A表达抑制结直肠癌发生发展的机制及临床意义，为结直肠癌的靶向治疗和相关药物的开发提供理论依据。

免疫细胞浸润对于预测结直肠癌的临床结果非常重要。整合素β7（ITGB7）表达在免疫细胞表面，对免疫细胞向肠道相关淋巴组织的归巢和在肠道上皮中的滞留至关重要。然而，ITGB7在结直肠癌发病中的作用尚未明确。我们发现与癌旁正常组织相比，肿瘤组织中的β7+细胞数量显著减少。利用公共平台的RNA表达数据，我们发现ITGB7高表达的患者表现出更长的生存期，更高水平的细胞毒性免疫细胞浸润，更低水平的体细胞拷贝数变化（SCNA），更低的APC和TP53突变频率以及对免疫治疗更好的响应。对单细胞测序（scRNA-seq）数据的分析表明，ITGB7主要在GALTB-IgA，cDC1-BATF3，细胞毒性NK细胞和T细胞中表达。我们还利用scRNA-seq数据揭示了ITGB7及其配体MAdCAM-1，VCAM-1和CDH1介导的可能的细胞间相互作用。此外，利用Apcmin/+自发和MC38原位两种小鼠结直肠癌模型，我们发现ITGB7缺失促进肿瘤发生发展，这可能是由于肿瘤浸润CD103+树突状细胞，IFN-γ+ CD8 T和NK细胞减少所致。综上，本研究发现ITGB7可以通过维持抗原呈递和细胞毒性免疫细胞的浸润来抑制结直肠癌的发生和发展，ITGB7可作为结直肠癌的潜在预后标志物和治疗靶标。