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

本研究的重点是激发性问题1：什么分子机制影响外显率 遗传了癌症易感基因的个体 Lynch综合征是一种易患结直肠癌（CRC）和其他癌症的遗传性疾病，影响>1 数百万美国人DNA错配修复（MMR）基因MLH 1、MSH 2、MSH 6和PMS 2的种系突变 引起MMR缺乏症（dMMR）和Lynch综合征。Lynch综合征CRCs的错义率显著升高 和小的in/del移码突变率。Lynch综合征的疾病外显率不完全， 广泛地。在这里，我们将从机制上阐明两个重要的问题林奇综合征CRC 外显率首先，免疫检查点阻断研究揭示了获得性免疫的重要作用 晚期和转移性Lynch综合征中抗肿瘤突变相关新抗原（MANAs）/dMMR 恶性肿瘤。然而，在恶性肿瘤前期和早期CRC的情况下，MANA负荷是 低得多，获得性免疫是否抑制Lynch综合征外显率？二、微生物群 具核梭杆菌（Fusobacterium nucleatum, F.细胞核）与CRC风险增加一致相关。对林奇 综合征CRCs，通过什么机制，F.细胞核促进外显？其中一部分 由于Lynch综合征小鼠模型几乎不产生CRCs，因此问题仍未得到解答。阐明本 影响Lynch综合征CRC外显率的机制，我们开发了第一个健壮的小鼠Lynch 综合征CRC模型。在目标1中，我们将阐明获得性免疫机制在减少小鼠-T细胞亚群中的作用。 Lynch综合征CRC外显率我们将检验新抗原疫苗接种降低小鼠总体免疫力假设 Lynch综合征CRC外显率，特别是来自Lgr 5+癌症干细胞的CRC。在目标2中 我们将阐明F.核仁区促进Lynch综合征CRC外显率。我们将测试 假设F. nucleatum促进IL 17 A驱动的Lynch综合征Lgr 5+癌干细胞增殖， 即F.细胞核单结合促进小鼠Lynch综合征CRC外显率，且接种 与F.细胞核抗原降低Lynch综合征小鼠中的定居和CRC外显率。总的来说这些 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外显率。

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.