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

本研究重点关注挑衅性问题 1：哪些分子机制影响外显率 遗传了癌症易感基因的人？ 林奇综合征是一种遗传性疾病，易患结直肠癌 (CRC) 和影响 >1 的其他癌症 百万美国人。 DNA 错配修复 (MMR) 基因 MLH1、MSH2、MSH6 和 PMS2 的种系突变 导致错配修复缺陷（dMMR）和林奇综合征。林奇综合征 CRC 错义显着增加 和小 in/del 移码突变率。林奇综合征的不完全疾病外显率各不相同 广泛。在这里，我们将从机制上阐明有关林奇综合征CRC的两个重要问题 外显率。首先，免疫检查点封锁研究揭示了适应性免疫的重要作用 对抗晚期肿瘤突变相关新抗原 (MANAs) 和转移性林奇综合征 /dMMR 恶性肿瘤。然而，在恶性肿瘤前期和早期 CRC 的情况下，MANA 负担是 低得多，适应性免疫会抑制林奇综合征的外显率吗？二、微生物群 具核梭杆菌 (F. nucleatum) 始终与 CRC 风险增加相关。对于林奇 CRC 综合征，具核梭菌促进外显率的机制是什么？部分这些 由于林奇综合征小鼠模型很少出现结直肠癌，因此问题仍未得到解答。为了阐明 影响 Lynch 综合征 CRC 外显率的机制，我们开发了第一个强大的 Lynch 小鼠 综合征CRC模型。在目标 1 中，我们将阐明适应性免疫机制的作用，以减少小鼠 - 林奇综合征 CRC 外显率。我们将测试新抗原疫苗接种会降低小鼠总体水平的假设 林奇综合征 CRC 外显率，特别是由 Lgr5 癌症干细胞产生的 CRC。目标 2 我们将阐明具核梭杆菌促进林奇综合征 CRC 外显率的机制。我们将测试 假设具核梭菌促进 IL17A 驱动的林奇综合征 Lgr5 癌症干细胞增殖， F. nucleatum mono-association 促进小鼠林奇综合征 CRC 外显率，并且疫苗接种 具核梭杆菌抗原可降低林奇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.