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

本研究的重点是挑衅性问题1：是什么分子机制影响外显？ 遗传癌症易感基因的人？ 林奇综合征是一种易患结直肠癌和其他癌症的遗传性疾病。 百万美国人。DNA错配修复基因MLH1、MSH2、MSH6和PMS2的种系突变 导致MMR缺乏症(DMMR)和林奇综合征。林奇综合征CRC的错误率大大提高 和较小的In/Del移码突变率。林奇综合征具有不完全的疾病外显性，这一点各不相同 广泛地。在这里，我们将机械地阐明有关Lynch综合征CRC的两个重要问题 洞察力。首先，免疫检查点阻断研究揭示了适应性免疫的重要作用 抗肿瘤突变相关新抗原(MNA)晚期和转移性林奇综合征/dMMR 恶性肿瘤。然而，在癌前和早期癌的情况下，MANA的负担是 更低的水平，适应性免疫是否会抑制林奇综合征的外显性？第二，微生物区系 核梭杆菌一直与结直肠癌的风险增加有关。对于Lynch 有核假单胞菌促进外显的机制是什么？部分原因是 问题仍然没有答案，因为林奇综合征小鼠模型很少发生CRC。为了澄清 影响Lynch综合征CRC外显率的机制，我们研制出了第一只健壮的小鼠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- 林奇综合征CRC外显性。我们将检验关于接种新抗原疫苗可降低小鼠总体体重的假设 林奇综合征CRC的外显性，特别是来自Lgr5癌症干细胞的CRC。在AIM 2 我们将阐明核盘藻促进Lynch综合征CRC外显性的机制。我们将测试 假设核杆菌促进IL17A驱动的林奇综合征Lgr5癌症干细胞增殖， 核单联合杆菌促进了小鼠Lynch综合征CRC的外显性，而疫苗接种 核杆菌抗原可减少Lynch综合征小鼠的定植和CRC外显率。总体来说，这些 研究将使用最先进的工具来阐明影响林奇综合征的获得性免疫机制 CRC穿透性。

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.