Mechanisms of Orthotopic Human Colorectal Cancer Growth in Immunocompetent Mice

 描述（由申请人提供）：结直肠癌（CRC）是全球癌症死亡的主要原因，转移性CRC的5年生存率仅为~ 15%。免疫治疗是治疗实体瘤的重要新途径。然而，迄今为止，它似乎对CRC基本无效，并且对人类CRC生长和转移的免疫机制知之甚少。在某种程度上，这是因为人类CRC异种移植模型只能在免疫缺陷小鼠宿主中产生，因为异种排斥。我们最近开发了趋化因子靶向小鼠模型（CTMM），这是一种在天然GI微环境中稳健建模原发性CRC而无需手术的新实验方法。通过使用趋化因子受体9/趋化因子25轴，CTMM运输人CRC细胞以在胃肠道中形成原位肿瘤。在这里，我们描述了小鼠ES细胞技术和CTMM的创新组合，以产生人CRC-小鼠嵌合体，这是免疫活性小鼠宿主中人原位CRC的第一个强大模型，用于机制研究，以解决潜在的肿瘤免疫学和潜在的体内治疗靶点。本申请的总体目标是了解人CRC细胞、肿瘤浸润免疫细胞和肠道微生物群之间的相互作用机制，以促进免疫活性宿主中的原位肿瘤生长。

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a leading cause of cancer death worldwide and 5-year survival for metastatic CRC is only ~15%. Immunotherapy is an important new approach to treat solid tumors. However, to date it appears largely ineffective against CRC, and the immune mechanisms underlying human CRC growth and metastasis are poorly understood. In part, this is because human CRC xenograft models could only be generated in immunodeficient mouse hosts because of xeno-rejection. We recently developed chemokine targeted mouse models (CTMM), a novel experimental approach to robustly model primary CRCs in the native GI micro- environment without requiring surgery. By using the Chemokine Receptor 9/ Chemokine 25 axis, CTMM traffics human CRC cells to form orthotopic tumors in the GI tract. Here, we describe an innovative combination of mouse ES cell technology and CTMM to generate human CRC-mouse chimeras, the first robust model of human orthotopic CRC in immunocompetent mouse hosts for mechanistic studies to address underlying tumor immunology and potential therapeutic targets in vivo. The overall goal of this application is to understand mechanisms of interaction between human CRC cells, tumor infiltrating immune cells, and the intestinal microbiota to promote orthotopic tumor growth in immunocompetent hosts.