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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要宿主与微生物的相互作用对癌症产生深远的影响。有据可查的感染证明了这一点促进癌症，以及通过疫苗接种或避免病原体来预防这些癌症的能力。然而，人类密集地居住着数万亿种通常有益的微生物，称为微生物群，也称为微生物群。具有通过诱导炎症或基因组不稳定性促进癌症的能力。此外，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治疗干预措施，例如检查点封锁。尽管取得了这些进展，但具体途径哪种微生物群形成促肿瘤免疫和抗肿瘤免疫仍然不明确，以及潜在的相关性这些发现对于特定类型的癌症尚不清楚。该提案的基本重点是从机械上定义了一种控制宿主-微生物群相互作用的新途径，以防止肿瘤进展并促进结直肠癌（CRC）免疫疗法的疗效。在最近根据已发表的数据（Goc 等人，Cell，2021），我们确定第 3 组先天淋巴细胞 (ILC3) 是 CRC 发生根本性改变，并有助于肿瘤进展和免疫治疗反应协调宿主-微生物群的相互作用。这些数据引发了一个基本假设：肠道 ILC3 在癌症中具有保护作用，但在结直肠癌中受到内在破坏，从而导致适应性功能失调免疫和微生物群的改变支持肿瘤进展和免疫治疗耐药性。我们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 CRC 中的 ILC3？； (2) ILC3通过哪些微生物和宿主途径发挥肿瘤保护作用进展？； (3) ILC3 保护免受免疫治疗的微生物和宿主途径是什么反抗？最后，我们将直接测试一些针对微生物群的干预策略，以限制肿瘤进展和破坏对癌症检查点抑制剂的抵抗力。这些实验的结果将为更好地了解癌症中宿主-微生物群的相互作用铺平道路，并可能激发新的发现通过调节宿主-微生物群相互作用来预防、治疗或治愈癌症的策略。