Investigating the impact of heterogeneous and homogenous neoantigen expression patterns on the anti-tumor immune response

项目总结/摘要 像检查点阻断疗法（CBT）这样的免疫疗法已经成为癌症治疗的突破， 在晚期疾病患者中观察到持久的反应。然而，大多数患者没有反应。 导致耐药性的因素在很大程度上仍不清楚。虽然临床数据显示新抗原负荷 与总体生存率和对CBT的反应正相关，有明显的新抗原 部分或无反应的人新出现的证据表明，新抗原表达的背景可以 影响免疫应答，其中具有由所有肿瘤细胞表达的克隆性新抗原的肿瘤引起强烈的免疫应答。 当肿瘤表现出高度的瘤内免疫时， 异质性（ITH），其中独特的新抗原由亚克隆表达，显示较弱的反应。如何 新抗原表达模式可以引发这样的不同应答是未知的。为了阐明 异质性表达的新抗原可以抑制免疫反应 模型以植入肿瘤，其中相同的一组新抗原均匀或不均匀地表达。 使用该系统，我们已经观察到，具有高ITH的肿瘤与具有高ITH的肿瘤相比具有弱免疫原性。 同质肿瘤有趣的是，我们的初步数据还表明，一个更早，更强大的T细胞， 如果弱免疫原性新抗原与非常免疫原性的新抗原一起表达，则可以诱导针对弱免疫原性新抗原的应答。 新抗原这种反应导致比在细胞系中观察到的更有效的肿瘤控制 仅表达强新抗原。这些初步数据使我们假设，较弱的抗肿瘤T- 针对异质表达的新抗原的细胞应答由树突状细胞的减少介导， 介导的T细胞引发。为了解决这个问题，我建议： 1.确定异质性新抗原表达对抗肿瘤T细胞应答的影响。 2.确定异质性肿瘤中抗肿瘤免疫应答较弱的机制基础。 通过解决这些目标，我们将获得关键的洞察力，为生产性的反， 肿瘤免疫应答，这将对免疫设计产生重大影响，特别是对于 高ITH患者的治疗。 这个项目的工作将促进我作为一个独立的科学家的发展，因为我获得了额外的 在麻省理工学院科赫研究所从事假设驱动科学的经验。我将与之互动， 来自癌症生物学研究领域当前和未来领导者的反馈，并与他们合作。而且这 环境强调基础癌症研究和生物工程的整合，以推动治疗发现， 将为我提供学习如何翻译我的发现的机会，特别是当我进一步发展我的 合作。最终，这个项目将训练我在整体的方法来问和解决基本的 癌症生物学的问题。

PROJECT SUMMARY/ABSTRACT Immunotherapies like checkpoint blockade therapy (CBT) have been a breakthrough for cancer treatment with durable responses observed in patients with advanced disease. However the majority of patients do not respond and factors leading to resistance remain largely unknown. While clinical data have shown that neoantigen load positively correlates with overall survival and response to CBT, there are patients with apparent neoantigens who show partial or no response. Emerging evidence suggests that the context of neoantigen expression can impact the immune response, where tumors with clonal neoantigens expressed by all tumor cells elicit robust anti-tumor immunity and correlate with CBT response while tumors exhibiting a high degree of intratumoral heterogeneity (ITH), where unique neoantigens are expressed by subclones, display weaker responses. How neoantigen expression patterns can elicit such dissimilar responses is not known. To elucidate how heterogeneously expressed neoantigens can dampen the immune response we created a novel murine tumor model to implant tumors where the same set of neoantigens are expressed homogeneously or heterogeneously. Using this system we have observed that tumors with high ITH are weakly immunogenic compared to homogenous tumors. Intriguingly, our preliminary data also suggest that an earlier and more robust T-cell response against a weakly immunogenic neoantigen can be induced if it is expressed with a very immunogenic neoantigen. This response leads to even more efficient tumor control than that observed in the cell line expressing only the strong neoantigen. These preliminary data led us to hypothesize that weaker anti-tumor T- cells responses against heterogeneously expressed neoantigens are mediated by a reduction in dendritic cell- mediated T cell priming. To address this question I propose to: 1. Determine the impact of heterogeneous neoantigen expression on anti-tumor T-cell responses. 2. Determine the mechanistic basis for weaker anti-tumor immune response in heterogeneous tumors. By addressing these aims we will gain critical insight into fundamental factors necessary for a productive anti- tumor immune response which would have significant impact on immunotherapeutic design, particularly for treatment of patients with high ITH. Work on this project will foster my development as an independent scientist as I gain additional experience performing hypothesis-driven science at the Koch Institute at MIT. I will interact with, receive feedback from and collaborate with current and future leaders in cancer biology research here. Furthermore, this environment stresses integration of basic cancer research and bioengineering to drive treatment discovery which will provide me with opportunities to learn how I can translate my discoveries, especially as I further develop my collaborations. Ultimately, this project will train me in the overall approach to asking and addressing fundamental questions in cancer biology.