Myeloid cell-expressed PTPN22 and anti-tumor immunity

项目总结 阻断检查点分子程序性细胞死亡1(PD-1)及其配体的免疫疗法 PD-L1给癌症治疗带来了革命性的变化；然而，相当数量的患者表现出对 免疫治疗，要么从头开始，要么在最初反应后疾病复发[1-3]。免疫疗法--难治性 病例促使人们深入了解耐药机制，这最终应导致制定新的战略 扩大临床疗效。原发耐药与肿瘤内缺乏免疫细胞浸润有关 微环境(TME)，这一观察促进了对肿瘤和宿主的更深入研究 调节自发性T细胞活化程度和向肿瘤部位渗透的因素。一个相关的 患者间异质性的来源是免疫调节中存在可变的多态(SNPs) 基因，其中许多以前被认为与自身免疫的倾向有关。 在这项拟议计划的F99阶段，我将评估针对与自身免疫相关的 基因以增加免疫治疗的疗效。酪氨酸蛋白磷酸酶非受体22型的单核苷酸多态 (PTPN22)基因被认为是人类自身免疫性疾病的最大风险，不包括突变 白细胞抗原基因座[4-6]。PTPN22负性调节多个免疫隔膜的激活， 功能丧失变异导致小鼠和人类免疫细胞激活增强[7-8]。这 免疫活性的增加归因于激活的CD8+T细胞的扩张，然而，据报道， DATE利用了全局基因敲除小鼠(KO)，混淆了PTPN22在其他细胞系中的特定作用 与抗肿瘤免疫有关，特别是髓系细胞。因此，我们研制了一种PTPN22fl/fl小鼠来研究其 通过条件性KO小鼠模型对不同免疫细胞类型的影响。我假设PTPN22的丢失 通过以下方式增强DC激活抗原特异性CD8+T细胞的能力：1)改进 TdLN或TME中的募集和/或生存信号，以及2)PTPN22在 巨噬细胞也可以增强抗肿瘤免疫。 在拟议计划的K00阶段，我的目标是确定管理抗肿瘤免疫的新靶点和 通过1)识别自身免疫相关SNPs的免疫治疗效果 随着肿瘤免疫浸润的增加以及2)这些靶点在肿瘤进展中的作用 以及通过使用条件性KO小鼠进行功能研究的免疫治疗反应。这项工作具有潜在的潜力 阐明新的治疗靶点以增强抗肿瘤免疫。我的最终目标是成为终身教职- 跟踪一家领先学术研究机构的教职员工，并开展由NIH资助的工作 通过阐明抗肿瘤免疫和开发新的免疫疗法来研究肿瘤免疫学领域。

PROJECT SUMMARY Immunotherapies that block the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 have revolutionized cancer treatment; however, a significant number of patients display resistance to immunotherapy, either de novo or with disease relapse after initial response [1-3]. Immunotherapy-refractory cases have prompted insight into mechanisms of resistance, which should ultimately lead to new strategies to expand clinical efficacy. Primary resistance is linked to lack of immune cell infiltration within the tumor microenvironment (TME), an observation which has prompted deeper investigation into the tumor and host factors that regulate the degree of spontaneous T cell activation and infiltration into tumor sites. One relevant source of inter-patient heterogeneity is the variable presence of polymorphisms (SNPs) in immune-regulatory genes, many of which have been linked previously to the propensity towards autoimmunity. In the F99 phase of this proposed plan, I will evaluate the utility of targeting an autoimmune-associated gene to increase immunotherapy efficacy. A SNP in the tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene is attributed with the greatest risk for autoimmune disease outside mutations in the human leukocyte antigen locus [4-6]. PTPN22 negatively regulates the activation of multiple immune compartments, with loss-of-function variants leading to heightened immune cell activation in mice and humans [7-8]. This increase in immune activity is attributed to the expansion of activated CD8+ T cells, however, work reported to date have utilized global knockout mice (KO), confounding the specific role of PTPN22 in other cell lineages relevant for anti-tumor immunity, in particular myeloid cells. We thus developed a PTPN22fl/fl mouse to study its effect in different immune cell types via conditional KO mouse models. I hypothesize that loss of PTPN22 augments the ability of DCs to activate antigen specific CD8+ T cells through 1) improved priming in the tdLN or recruitment to and/or survival signaling in the TME and that 2) deletion of PTPN22 in macrophages also may potentiate anti-tumor immunity. In the K00 phase of the proposed plan, I aim to identify novel targets governing anti-tumor immunity and immunotherapy efficacy by 1) identifying autoimmune related SNPs whose loss of function variants correlate with increased tumor immune infiltration and 2) characterizing the effect of these targets on tumor progression and immunotherapy response through functional studies using conditional KO mice. This work holds the potential to elucidate novel therapeutic targets to potentiate anti-tumor immunity. My ultimate goal is to become a tenure- track faculty member at a leading academic research institution and conduct NIH funded work contributing to the field of tumor immunology by elucidating anti-tumor immunity and developing novel immunotherapies.