Project 3: Modeling and overcoming resistance to melanoma immunotherapy

项目3摘要 我们已经开始在确定导致初级和获得性抗药性的机制方面取得进展。 在分子水平上进行PD-1/L1治疗。在这个项目中，我们打算描述它们的生物学特征，发现它们是如何 在机械理解的基础上克服阻力，并研究这种知识如何改进 病人护理。在目标1中，我们将开发体外和体内模型来研究分子定义的生物学 阻力机制，目标是提供对它们如何调解的完全机械性理解 抵抗。这是基于我们发现的干扰素纯合子功能丧失(LoF)突变 (干扰素)受体途径和抗原提呈机制(APM)在原发性和非霍奇金淋巴瘤患者活检组织中的表达 对PD-1阻断治疗的获得性抵抗，两者都与来自其他组的数据相证实。有了这个 信息，我们将能够测试克服抗PD-1/L1耐药性的组合方法 心理治疗。这些方法包括旨在诱导可能激活这一途径的局部干扰素反应的方法 下游，如Toll样受体(TLR)或JAK1/2基因敲除模型中的MDA5激动剂，以及激活 B2M基因敲除模型中的自然杀伤(NK)细胞。在目标2中，我们将研究一种新的癌细胞--内源性 P21相关蛋白4(PAK4)表达介导的T细胞排斥机制 最近通过比较富含T细胞和缺乏T细胞的患者活检组织中的基因表达发现了 用抗PD-1治疗黑色素瘤。我们将研究导致T细胞排斥的机制 在小鼠模型中，我们将分析从患者获得的活检组织中的机制 参加了一项结合PAK4抑制剂KPT-9274和抗PD-1抗体nivolumab的临床试验。 这两个目标的样本分析将受益于与其他两个调查人员的合作 本P01的项目和核心。总而言之，本项目将分析明确的治疗机制 抵抗癌症免疫疗法，以提供对其效果的更好理解，并展示如何 使用合理设计的组合研究克服阻力。 1

PROJECT 3 ABSTRACT We have started to make progress in defining mechanisms that lead to primary and acquired resistance to anti- PD-1/L1 therapy at the molecular level. In this Project, we propose to characterize their biology, discover how to overcome resistance based on mechanistic understanding, and study how this knowledge can improve patient care. In Aim 1, we will develop in vitro and in vivo models to study the biology of molecularly-defined resistance mechanisms with the goal of providing full mechanistic understanding of how they mediate resistance. This is based on our discovery of homozygous loss of function (LoF) mutations in the interferon (IFN) receptor pathway and in the antigen presenting machinery (APM) in biopsies of patients with primary and acquired resistance to PD-1 blockade therapy, both confirmed with data from other groups. With this information, we will be in the position to test combination approaches to overcome resistance to anti-PD-1/L1 therapy. These include approaches aimed at inducing a local IFN response that may activate this pathway downstream, such as toll-like receptor (TLR) or MDA5 agonists in JAK1/2 knockout models, and activating natural killer (NK) cells in B2M knockout models. In Aim 2, we will study a new cancer cell-intrinsic mechanisms of T cell exclusion mediated by the expression of the p21 associated kinase 4 (PAK4), which we have recently uncovered by comparing gene expression in T cell-rich versus T cell-poor biopsies of patients with melanoma on therapy with anti-PD-1. We will examine the mechanisms leading to T cell exclusion induced by PAK4 in mouse models, and we will analyze the mechanisms in biopsies obtained from patients enrolled in a clinical trial combining the PAK4 inhibitor KPT-9274 and the anti-PD-1 antibody nivolumab. Sample analyses for the two aims will benefit from the collaboration with investigators from the other two projects and cores of this P01. In conclusion, this Project will analyze defined mechanisms of therapeutic resistance to cancer immunotherapy to provide improved understanding on their effects, and show how to overcome the resistance using rationally designed combination studies. 1