Neoantigen Vaccination for Lynch Syndrome Immunoprevention

Lynch综合征（LS）是一种易患结直肠癌（CRC）的遗传性疾病， 数百万美国人DNA错配修复（MMR）基因的种系突变，主要是MLH 1和MSH 2， 导致DNA错配修复缺陷（dMMR）和LS。LS CRC的小 插入/缺失移码和错义突变。升高的dMMR突变率导致一些突变， 在不同患者的肿瘤中反复出现。例如，人TGFβR2基因具有一个编码poly（A）的 重复，并且在>60%的LS dMMR CRC中反复鉴定出相同的“共享”移码突变。在这里， 我们将使用最先进的工具系统地描述复发性LS小鼠和人类癌前病变， 新抗原，测试用频繁突变的“共享”免疫原性新抗原接种是否减少LS 小鼠结直肠癌的发生率，并阐明适应性免疫机制的CRC免疫预防。目标1 我们将全面描述Lynch综合征小鼠中频繁突变的复发性新抗原， 结直肠粘膜和腺瘤。这将为癌前结肠dMMR免疫编辑提供见解 机制，dMMR新抗原出现的时间和顺序，并系统地描述了 大多数免疫原性复发共享dMMR新抗原疫苗靶向LS小鼠CRC免疫预防。 在目标2中，我们将检验复发性新抗原疫苗接种减少小鼠Lynch综合征的假设。 错配修复缺陷的结肠粘膜上皮细胞。这将有助于深入了解dMMR的机制 结肠粘膜免疫编辑，并测试dMMR复发性新抗原疫苗的有效性和安全性 使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 复发性新抗原疫苗接种可降低小鼠Lynch综合征结直肠肿瘤负荷。这将 评估Lynch的dMMR复发性腺瘤新抗原疫苗策略的有效性和安全性 综合征免疫预防，并提供深入了解dMMR免疫编辑的机制。最后在 目的4系统描述Lynch综合征患者腺瘤复发的新抗原。这将 描述可用于LS患者肿瘤疫苗的最有希望的候选复发性新抗原 临床试验和深入了解dMMR免疫编辑机制。我们的总体目标是发展有效的， 基于安全机制的新抗原疫苗接种策略用于Lynch综合征CRC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.