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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：
10707106
负责人：
Gregory F Sonnenberg
金额：
$ 56.85万
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/10707106
关键词：
Address Automobile Driving Cancer Model Cells Cessation of life Colorectal Cancer Cytoprotection Data Evolution Exhibits Failure Frequencies Functional disorder Genomic Instability Health Health Care Costs Histocompatibility Antigens Class II Homeostasis Human Immune checkpoint inhibitor Immunity Immunologics Immunotherapy Impairment Infection Inflammation Intervention Intestines Invaded Knowledge Lymphocyte Lymphoid Cell Malignant Neoplasms Microbe Molecular Mus Newly Diagnosed Pathway interactions Population Publishing Regulation Resistance Role Seminal Shapes T-Lymphocyte Testing Therapeutic Therapeutic Intervention Tissues Tumor Cell Invasion Tumor Immunity Tumor Promotion 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 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