Investigating Immune Responses to Neoantigen Cancer Vaccines using In Vivo Functionalized Lineage

项目摘要 肺癌是全世界与癌症相关的死亡的主要原因，表明迫切需要 有效和持久的治疗方法。免疫检查点抑制剂，它可以阻断T细胞功能的负面调节， 有可能在肺癌患者中产生持久的反应。然而，只有少数患者 对这些疗法有反应，其肿瘤最初对治疗有反应的患者中约有50%最终对治疗有反应 产生后天抵抗力。临床研究已经确定了肿瘤非同义性之间的相关性 多种癌症类型的突变负担和对免疫检查点抑制剂的反应。然而，大多数 现有的肺癌临床前小鼠模型不能概括肺癌突变的复杂性 人类癌症，重要的是，这些模型中的肿瘤对免疫检查点抑制没有反应。 部分由于缺乏可用的模型，初级和获得性免疫抵抗的机制 肺癌中的检查点抑制尚不完全清楚，克服耐药性的策略是 缺乏。为了应对这一挑战，我们开发了新的kras突变肺原位小鼠模型。 腺癌概括了人类疾病的特征，对于研究肿瘤-免疫相互作用是必不可少的， 包括肿瘤突变情况以及对免疫的反应性和获得性抵抗力 检查点抑制。利用这些新的小鼠肺癌模型，我的目标是研究 对这些广泛使用的新肺癌疗法(F99期)的抵抗力。我将检验最重要的假设 不同的基因改变和转录程序导致抗原提呈缺陷和 新抗原丢失是对ICIS产生获得性耐药的主要机制，这些机制导致了 肿瘤细胞在肿瘤微环境中的外在耐药特征。我将研究一下 获得性耐药性的遗传和转录驱动因素，重点关注抗原处理和 介绍(目标1.2.A)。我还将研究新抗原丢失是否可以介导肺部获得性耐药。 癌症(目标1.2.B)。作为一名博士后(K00阶段)，我计划致力于改进免疫疗法的方法 肺癌将受益于比目前受益的患者更广泛的人群，特别是 通过研究诱导组织驻留记忆T细胞的个性化新抗原疫苗的有效性 (目标2)。这里描述的目标将确定抵抗检查点治疗的驱动因素并探索方法 在目前没有从已批准的免疫疗法中受益的患者中使用新抗原疫苗，产生 将免疫疗法的好处扩大到更广泛的患者群体的战略。

Project Summary Lung cancer is the leading cause of cancer related deaths worldwide, demonstrating the pressing need for effective and lasting treatments. Immune checkpoint inhibitors, which block negative regulators of T cell function, have the potential to generate lasting responses in lung cancer patients. However, only a minority of patients respond to these therapies and ~50% of patients whose tumors initially respond to therapy eventually develop acquired resistance. Clinical studies have identified correlations between tumor non-synonymous mutation burden and response to immune checkpoint inhibitors across multiple cancer types. However, most existing pre-clinical mouse models of lung cancer do not recapitulate the complexity of mutational landscapes in human cancers, and importantly, the tumors in these models do not respond to immune checkpoint inhibition. Due in part to the lack of available models, mechanisms of primary and acquired resistance to immune checkpoint inhibition in lung cancer are not fully understood and strategies to overcome resistance are lacking. To address this challenge, we developed novel orthotopic mouse models of Kras mutant lung adenocarcinoma that recapitulate features of human disease essential for studying tumor-immune interactions, including the tumor mutational landscape as well as responsiveness and acquired resistance to immune checkpoint inhibition. Using these novel models of murine lung cancer, my goal is to investigate mechanisms of resistance to these new widely-used lung cancer therapies (F99 phase). I will test the overarching hypothesis that diverse genetic alterations and transcriptional programs resulting in antigen presentation defects and neoantigen loss are major mechanisms of acquired resistance to ICIs and that these drive the emergence of tumor-cell extrinsic features of resistance in the tumor microenvironment. I will investigate the spectrum of genetic and transcriptional drivers of acquired resistance, focusing on defects in antigen processing and presentation (Aim 1.2.A). I will also investigate whether neoantigen loss can mediate acquired resistance in lung cancer (Aim 1.2.B). As a post-doc (K00 phase), I plan to work on approaches to improve immunotherapies for lung cancer to expand their benefits to a broader patient population than those who currently benefit, specifically by investigating the efficacy of personalized neoantigen vaccines that induce tissue resident memory T cells (Aim 2). The aims described here will identify drivers of resistance to checkpoint therapy and explore methods to use neoantigen vaccines in patients that currently do not benefit from approved immunotherapies, yielding strategies to expand immunotherapy benefits to a broader patient pool.