Neoantigen Vaccination for Lynch Syndrome Immunoprevention

林奇综合征(LS)是一种易患结直肠癌(CRC)的遗传性疾病，影响不止一个 百万美国人。DNA错配修复(MMR)基因的种系突变，主要是MLH1和MSH2， 导致DNA错配修复缺陷(DMMR)和LS。LS CRC具有极高数量的小型 插入/缺失移码和错义突变。DMMR突变率升高导致一些突变 反复出现在不同患者的肿瘤中。例如，人转化生长因子βR2基因具有Poly(A)编码 重复，相同的“共享”移码突变在&gt；60%的LS dMMR癌中被反复发现。这里, 我们将使用最先进的工具系统地描绘复发的LS小鼠和人类癌前病变 新抗原，测试用频繁突变的“共享”免疫原新抗原接种是否能减少LS 小鼠CRC的外显性，并阐明CRC免疫预防的获得性免疫机制。在目标1中 我们将全面描述Lynch综合征小鼠频繁突变的复发新抗原 结直肠粘膜和腺瘤。这将提供对癌前结肠dMMR免疫编辑的见解 DMMR新抗原出现的机制、时间和顺序，并系统地描绘了 大多数免疫原性复发共享dMMR新抗原疫苗靶点用于LS小鼠CRC的免疫预防。 在目标2中，我们将检验反复接种新抗原疫苗可减少小鼠林奇综合征的假设。 结肠粘膜错配修复缺陷上皮细胞。这将使我们对dMMR的机制有深入的了解 结肠黏膜免疫编辑，并测试dMMR复发新抗原疫苗的有效性和安全性 利用最早的新抗原突变进行LS免疫预防的策略。在目标3中，我们将检验假设 反复接种新抗原可减轻小鼠Lynch综合征结直肠癌的负担。这将是 林奇dMMR复发性腺瘤疫苗策略的有效性和安全性评价 症状免疫预防和对dMMR免疫编辑机制的洞察。最后，在 目的系统地描述Lynch综合征患者腺瘤复发的新抗原。这将是 最有希望用于LS患者肿瘤疫苗的候选复发新抗原 临床试验和对dMMR免疫编辑机制的见解。我们的总体目标是开发有效的、 基于安全机制的新抗原接种策略用于Lynch综合征CRC的免疫预防。

Lynch syndrome (LS) is a genetic disease predisposing to colorectal cancer (CRC) that affects more than one million Americans. Germline mutations in DNA mismatch repair (MMR) genes, primarily MLH1 and MSH2, cause deficient DNA mismatch repair (dMMR) and LS. LS CRCs have exceptionally high numbers of small insertion/deletion frameshift and missense mutations. Elevated dMMR mutation rates cause some mutations to recurrently arise in tumors from different patients. For example, the human TGFβR2 gene has a poly(A) coding repeat, and the same “shared” frameshift mutation is recurrently identified in >60% of LS dMMR CRCs. Here, we will use state of the art tools to systematically delineate recurrent LS mouse and human pre-malignant neoantigens, test whether vaccination with frequently mutated “shared” immunogenic neoantigens reduces LS mouse CRC penetrance, and elucidate adaptive immune mechanisms for CRC immunoprevention. In Aim 1 we will comprehensively delineate frequently mutated recurrent neoantigens in Lynch syndrome mouse colorectal mucosa and adenomas. This will provide insights into pre-malignant colon dMMR immunoediting mechanisms, the timing and sequence of dMMR neoantigen appearance, and systematically delineate the most immunogenic recurrent shared dMMR neoantigen vaccine targets for LS mouse CRC immunoprevention. In Aim 2 we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome mismatch repair deficient epithelial cells in colon mucosa. This will give insights into the mechanism of dMMR colon mucosal immunoediting, and test the efficacy and safety of a dMMR recurrent neoantigen vaccine strategy using the earliest neoantigen mutations for LS immunoprevention. In Aim 3, we will test the hypothesis that recurrent neoantigen vaccination reduces mouse Lynch syndrome colorectal tumor burden. This will evaluate the efficacy and safety of a dMMR recurrent adenoma neoantigen vaccine strategy for Lynch syndrome immunoprevention and provide insights into the mechanisms of dMMR immunoediting. Finally, in Aim 4 we will systematically delineate Lynch syndrome patient adenoma recurrent neoantigens. This will delineate the most promising candidate recurrent neoantigens that can be used for LS patient tumor vaccine clinical trials and give insights into dMMR immunoediting mechanisms. Our overall goal is to develop effective, safe mechanism based neoantigen vaccination strategies for Lynch syndrome CRC immunoprevention.