Innate lymphoid cell regulation of the host-microbiota interactions in cancer

先天淋巴细胞对癌症中宿主-微生物群相互作用的调节

• 批准号: 10522877
• 负责人: Gregory F Sonnenberg
• 金额: $ 58.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522877
• 关键词: Address; Automobile Driving; Cancer Model; Cells; Cessation of life; Colorectal Cancer; Data; Diagnosis; Evolution; Exhibits; Failure; Frequencies; Functional disorder; Genomic Instability; Genomics; Health; Health Care Costs; Histocompatibility Antigens Class II; Homeostasis; Human; Immune checkpoint inhibitor; Immunity; Immunologics; Immunotherapy; Impairment; Infection; Inflammation; Intervention; Intestines; Knowledge; Lymphocyte; Lymphoid Cell; Malignant Neoplasms; Microbe; Molecular; Mus; Pathway interactions; Population; Publishing; Regulation; Resistance; Role; Seminal; Shapes; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor Cell Invasion; Tumor Immunity; United States; Vaccination; adaptive immunity; anti-PD1 therapy; beneficial microorganism; cancer type; checkpoint therapy; cytokine; exhaustion; experimental study; gut inflammation; gut microbiota; host microbiota; host-microbe interactions; human model; immune checkpoint blockade; improved; microbial; microbial host; microbiota; mouse model; neoplasm immunotherapy; novel; novel strategies; novel therapeutic intervention; pathogen; phenotypic biomarker; prevent; response; socioeconomics; success; therapeutic target; transcription factor; tumor microenvironment; tumor progression

PROJECT ABSTRACT Host-microbe interactions profoundly impact cancer. This is exemplified by well-documented infections that promote cancer, and the ability to prevent these cancers through vaccination or pathogen avoidance. However, humans are densely colonized with trillions of normally beneficial microbes, termed the microbiota, which also have the ability to promote cancers through the induction of inflammation or genomic instability. Further, recent seminal studies demonstrated that intestinal microbiota are also required for anti-tumor immunity in the context of therapeutic interventions, such as checkpoint blockade. Despite these advances, the specific pathways by which microbiota shape pro- versus anti-tumor immunity remain poorly defined, and the potential relevance of these findings to specific types of cancer are unknown. The fundamental focus of this proposal is to mechanistically define a novel pathway that controls host-microbiota interactions to protect from tumor progression and promote the efficacy of immunotherapies in colorectal cancer (CRC). In recently published data (Goc et al., Cell, 2021), we have determined that group 3 innate lymphoid cells (ILC3s) are fundamentally altered in CRC and contribute to tumor progression and immunotherapy responsiveness by coordinating host-microbiota interactions. These data provoke a fundamental hypothesis that intestinal ILC3s are protective in cancer, but become inherently disrupted in CRC, subsequently driving dysfunctional adaptive immunity and alterations to the microbiota that support tumor progression and immunotherapy resistance. We will mechanistically test this hypothesis by asking the following specific questions: (1) What drives dysfunction of ILC3s in CRC?; (2) What are the microbial and host pathways by which ILC3s protect from tumor progression?; And (3) What are the microbial and host pathways by which ILC3s protect from immunotherapy resistance? Finally, we will directly test a number of interventional strategies that target the microbiota to limit tumor progression and break resistance to cancer checkpoint inhibitors. Results from these experiments will pave the way for a greater understanding of host-microbiota interactions in cancer, and could provoke novel preventative, therapeutic or curative strategies in cancer by modulating host-microbiota interactions.

项目摘要 宿主-微生物的相互作用对癌症产生了深远的影响。这一点以有充分记录的感染为例 促进癌症，以及通过接种疫苗或避免病原体来预防这些癌症的能力。然而， 人类密集地栖息着数以万亿计的正常有益的微生物，被称为微生物区系，它也 有能力通过诱导炎症或基因组不稳定来促进癌症。更进一步，最近 开创性研究表明，肠道微生物群也是抗肿瘤免疫所必需的。 例如检查站封锁等治疗性干预措施。尽管取得了这些进展，但通过 哪种微生物区系形态的亲肿瘤免疫和抗肿瘤免疫仍未明确，以及 这些发现对特定类型的癌症是未知的。这项建议的基本重点是 机械地定义了一种控制宿主-微生物群相互作用的新途径，以防止 促进结直肠癌(CRC)免疫治疗的疗效。在最近 发表的数据(Goc等人，Cell，2021)，我们已经确定了第3组固有淋巴样细胞(ILC3)是 在结直肠癌中发生根本性改变，并通过以下方式促进肿瘤进展和免疫治疗反应 协调宿主-微生物区系的相互作用。这些数据引发了一个基本假设，即肠道中的ILC3 在癌症中具有保护性，但在CRC中固有地被破坏，随后推动功能失调的适应性 免疫和支持肿瘤进展和免疫治疗抵抗的微生物区系的变化。我们 我将通过提出以下具体问题来机械地检验这一假设：(1)是什么导致了功能障碍 ILC3在结直肠癌中的作用；(2)ILC3通过哪些微生物和宿主途径保护肿瘤 进展？；以及(3)ILC3保护免疫治疗的微生物和宿主途径是什么 抵抗？最后，我们将直接测试一些针对微生物区系的干预策略，以限制 肿瘤进展和对癌症检查点抑制剂的破坏抵抗。这些实验的结果将 为更好地了解癌症中宿主-微生物区系的相互作用铺平了道路，并可能引发新的 通过调节宿主-微生物区系的相互作用来预防、治疗或治愈癌症的策略。