Effects of common polymorphisms in immune sensors in tumor immunosurveillance

免疫传感器常见多态性在肿瘤免疫监视中的作用

• 批准号: 8724457
• 负责人: Jose R Conejo-Garcia
• 金额: $ 36.66万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724457
• 关键词: Affect; Autoimmune Diseases; Cancer Patient; Cells; Collection; Data; Development; Dominant-Negative Mutation; Event; Exhibits; Flagellin; Galectin 1; General Population; Genetic Polymorphism; Goals; Hand; Homeostasis; Human; Immune; Immune response; Immune system; Immunologic Monitoring; Immunologic Surveillance; Immunosuppressive Agents; Immunotherapeutic agent; Individual; Inflammatory; Interleukin-17; Intervention; Intestines; Lead; Legionella; Leukocytes; Life; Ligands; Location; Lymphocyte; Malignant - descriptor; Malignant neoplasm of ovary; Mammary Neoplasms; Mediating; Medicine; Modeling; Mus; Mutation; Oncogenic; Ovarian Carcinoma; Patients; Pattern recognition receptor; Phenotype; Pneumonia; Population; Predisposition; Production; Receptor Gene; Recruitment Activity; Regulatory T-Lymphocyte; Research; Role; Sampling; Signal Transduction; Solid Neoplasm; Source; Specimen; Suspension substance; Suspensions; T cell differentiation; T-Lymphocyte; TLR5 gene; Testing; The Cancer Genome Atlas; Time; Toll-like receptors; Tumor Bank; Tumor Immunity; Variant; Work; base; cancer diagnosis; clinically relevant; commensal microbes; cytokine; loss of function; malignant breast neoplasm; microorganism; novel; outcome forecast; pressure; prognostic; public health relevance; receptor; response; sensor; tool; tumor; tumor growth; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): The most frequent loss-of-function for any TLR is the R392X variant of TLR5, which has a dominant-negative effect, affects ~7-10% of the general population, and is relevant for the function of the immune system. Here, we will elucidate for the first time how mechanisms of tumor immunosurveillance are differentially modulated in the absence of TLR5 signaling. Key experimental findings supporting this proposal have been: 1) The recognition that TLR5-deficiency confers superior immune protection against malignant progression in mice, both in terms of quality and magnitude; 2) analysis of emerging data from TCGA project indicating that TLR5- deficient patients survive in higher proportions after two years of an ovarian cancer diagnosis, compared to wild-type individuals; 3) the identification of a dissimilar population of ?¿ T cells that accelerates malignant progression in TLR5+ hosts, but exerts protective activity in TLR5-deficient individuals. Based on these and other of our findings, our central hypothesis is that TLR5-deficiency, through dissimilar interactions with commensal microorganisms (the only endogenous source of flagellin), results in significant functional differences in ?¿ T cells, which modulate systemic mechanisms of immune surveillance, leading to different immune protection against malignant progression. In Aim 1, we will determine how ?¿ T cells influence tumor progression in wild-type vs. TLR5-deficient individuals. These results will dissect the suppressive mechanisms whereby ?¿ T cells generated in the presence of TLR5 signaling promote tumor growth, while their counterpart in TLR5-deficient hosts delay malignant development. In Aim 2, we will elucidate why ?¿ T cells acquire a different phenotype in TLR5-deficient tumor-bearing hosts. Because the ligand of TLR5 is a bacterial product, these results will elucidate how microbiota (carriers of the only endogenous ligand) drives the differentiation of ?¿ T cells that determine immunosurveillance responses. In Aim 3, we will define differences in anti-tumor immunity between human TLR5-deficient and wild-type cancer patients, using our bank of viable ovarian and breast cancer dissociated specimens. Our work will exert a profound effect in the field by elucidating how a significant segment of the general population may orchestrate different anti-tumor immune microenvironments that could make them more responsive to specific immunotherapeutic interventions. Furthermore, this research could pave the way for understanding how millions of individuals may be more susceptible (or show enhanced protection) to develop aggressive tumors in response to mutagenic events that remain asymptomatic in other people.

描述（由申请人提供）：任何TLR最常见的功能丧失是TLR5的R392X变体，其具有显性负性作用，影响约7-10%的普通人群，并且与免疫系统功能相关。在这里，我们将首次阐明在TLR5信号缺失的情况下，肿瘤免疫监视的机制是如何被差异调节的。支持这一建议的关键实验发现有：1)认识到tlr5缺陷在质量和程度上都赋予小鼠对恶性进展的优越免疫保护；2) TCGA项目的新数据分析表明，与野生型个体相比，TLR5缺陷患者在卵巢癌诊断两年后的存活率更高；3)识别