(PQ1) Adaptive immune and microbial mechanisms regulating Lynch syndrome penetrance

(PQ1) 调节林奇综合征外显率的适应性免疫和微生物机制

• 批准号: 10229450
• 负责人: Steven M Lipkin
• 金额: $ 50.32万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-04 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229450
• 关键词: Adaptive Immune System; Address; Affect; American; Antigens; Bacteria; CD4 Positive T Lymphocytes; Cancer-Predisposing Gene; Cell Line; Cells; Coculture Techniques; Colon; Colonic Adenoma; Colonic Neoplasms; Colorectal; DNA; Data; Disease; Frameshift Mutation; Fusobacterium nucleatum; Genes; Genetic Diseases; Germ-Line Mutation; Hereditary Nonpolyposis Colorectal Neoplasms; Immune; Individual; Inherited; Interleukin-17; Intestinal Neoplasms; Knowledge; LGR5 gene; MAP Kinase Gene; MLH1 gene; MSH2 gene; MSH6 gene; Malignant Neoplasms; Membrane; Mismatch Repair; Mismatch Repair Deficiency; Modeling; Molecular; Mus; Mutate; Mutation; Neoplasms; Organoids; PD-1 blockade; PMS2 gene; Pathway interactions; Patients; Penetrance; Peptides; Recurrence; Resistance; Resistance development; Risk; Role; STAT3 gene; Signal Transduction; Small Intestinal Neoplasm; Testing; Vaccination; Vesicle; adaptive immunity; adenoma; cancer stem cell; cytokine; gene repair; immune checkpoint blockade; immunogenic; in vivo; insight; microbial; microbiota; mouse model; neoantigen vaccination; neoantigens; premalignant; stem cell proliferation; stem cells; tool; tumor; tumorigenesis; tumorigenic

This study focuses on Provocative Question 1: What molecular mechanisms influence penetrance in individuals who inherit a cancer susceptibility gene? Lynch syndrome is a genetic disease predisposing to colorectal (CRC) and other cancers that affects >1 million Americans. Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause MMR deficiency (dMMR) and Lynch syndrome. Lynch syndrome CRCs have greatly elevated missense and small in/del frameshift mutation rates. Lynch syndrome has incomplete disease penetrance that varies widely. Here we will mechanistically elucidate two important questions about Lynch syndrome CRC penetrance. First, immune checkpoint blockade studies have revealed important roles for adaptive immunity against tumor mutation associated neoantigens (MANAs) in late stage and metastatic Lynch syndrome /dMMR malignancies. However, in the setting of pre-malignancy and early-stage CRCs, where the MANA burden is much lower, does adaptive immunity suppress Lynch syndrome penetrance? Second, the microbiota Fusobacterium nucleatum (F. nucleatum) is consistently associated with increased CRC risk. For Lynch syndrome CRCs, what are the mechanisms through which F. nucleatum promotes penetrance? In part these questions remain unanswered because Lynch syndrome mouse models develop few CRCs. To elucidate the mechanisms influencing Lynch syndrome CRC penetrance, we have developed the first robust mouse Lynch syndrome CRC model. In Aim 1 we will elucidate the roles of adaptive immunity mechanisms to reduce mouse - Lynch syndrome CRC penetrance. We will test hypotheses that neoantigen vaccination reduces overall mouse Lynch syndrome CRC penetrance, and specifically for CRCs that arise from Lgr5+ cancer stem cells. In Aim 2 we will elucidate mechanisms of F. nucleatum to promote Lynch syndrome CRC penetrance. We will test hypotheses that F. nucleatum promotes IL17A driven Lynch Syndrome Lgr5+ cancer stem cell proliferation, that F. nucleatum mono-association promotes mouse Lynch syndrome CRC penetrance, and that vaccination with F. nucleatum antigens reduces colonization and CRC penetrance in Lynch Syndrome mice. Overall these studies will use state-of-the-art tools to elucidate adaptive immune mechanisms influencing Lynch syndrome CRC penetrance.

这项研究的重点是挑衅性问题1：哪些分子机制会影响渗透 继承癌症敏感性基因的个人？ 林奇综合征是一种遗传疾病，易于结直肠疾病（CRC）和其他影响> 1的癌症 百万美国人。 DNA不匹配修复（MMR）基因MLH1，MSH2，MSH6和PMS2中的种系突变 导致MMR缺乏症（DMMR）和林奇综合征。林奇综合征CRC的错义大大提升 和较小的/del frameshift突变率。林奇综合征的疾病不完整，有所不同 广泛。在这里，我们将机械地阐明有关林奇综合征CRC的两个重要问题 外观。首先，免疫检查点封锁研究揭示了自适应免疫的重要作用 在后期与肿瘤突变相关的新抗原（Manas）和转移性林奇综合征 /DMMR 恶性肿瘤。但是，在现场和早期CRC的环境中，法力负担为 低得多，适应性免疫会抑制林奇综合征的渗透性吗？其次，微生物群 核细菌核（F. nucleatum）始终与CRC风险增加有关。对于林奇 综合征CRC，F。Nucleatum促进外渗的机制是什么？部分 由于Lynch综合征鼠标模型会产生很少的CRC，因此问题仍然没有得到答复。阐明 影响Lynch综合征CRC渗透率的机制，我们开发了第一个健壮的小鼠lynch 综合征CRC模型。在AIM 1中，我们将阐明自适应免疫机制减少小鼠的作用 - 林奇综合征CRC渗透。我们将检验假设新抗原疫苗接种的假设减少了整体小鼠 Lynch综合征CRC渗透性，特别是针对LGR5+癌症干细胞引起的CRC。在目标2中 我们将阐明F. nucleatum的机制来促进Lynch综合征CRC渗透率。我们将测试 假设F. nutleatum促进IL17A驱动的Lynch综合征LGR5+癌症干细胞增殖， F. nucleatum Mono-Cosociation促进了小鼠Lynch综合征CRC渗透性，并疫苗接种 使用F. nucleatum抗原可减少林奇综合征小鼠的定殖和CRC渗透率。总体而言 研究将使用最先进的工具来阐明影响林奇综合征的适应性免疫机制 CRC渗透。