Myeloid cell-expressed PTPN22 and anti-tumor immunity

项目摘要 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已经彻底改变了癌症治疗;然而，大量患者显示出对PD-L1的耐药性。 免疫治疗，无论是从头或疾病复发后，初步反应[1-3]。免疫治疗难治性 这些病例促使人们深入了解耐药机制，这最终将导致新的战略， 扩大临床疗效。原发性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T细胞活化和浸润到肿瘤部位的程度的因子。一个相关 患者间异质性的来源是免疫调节基因中多态性（SNP）的可变存在。 基因，其中许多基因以前曾与自身免疫倾向有关。 在这个计划的F99阶段，我将评估靶向自身免疫相关的 基因，以提高免疫治疗的疗效。酪氨酸蛋白磷酸酶非受体22型中的SNP （PTPN 22）基因被认为是人类自身免疫性疾病突变以外的最大风险。 白细胞抗原位点[4-6]。PTPN 22负调节多个免疫区室的激活， 在小鼠和人类中，功能丧失变体导致免疫细胞活化增强[7-8]。这 免疫活性的增加归因于活化的CD 8 + T细胞的扩增，然而，据报道， 迄今为止，已经利用了全基因敲除小鼠（KO），混淆了PTPN 22在其他细胞谱系中的特定作用 与抗肿瘤免疫相关，特别是骨髓细胞。因此，我们开发了PTPN 22 fl/fl小鼠以研究其在小鼠中的表达。 通过条件性KO小鼠模型在不同免疫细胞类型中的作用。我推测PTPN 22的缺失 增强DC活化抗原特异性CD 8 + T细胞的能力，通过1）改善免疫细胞中的引发， tdLN或募集和/或TME中的存活信号传导，以及2）TME中PTPN 22的缺失， 巨噬细胞也可增强抗肿瘤免疫。 在拟议计划的K 00阶段，我的目标是确定控制抗肿瘤免疫的新靶点， 通过1）鉴定自身免疫相关的SNP，其功能丧失变体与免疫治疗功效相关， 具有增加的肿瘤免疫浸润和2）表征这些靶点对肿瘤进展的作用 和免疫治疗反应通过使用条件性KO小鼠的功能研究。这项工作有可能 阐明增强抗肿瘤免疫的新治疗靶点。我的最终目标是成为终身教职- 跟踪领先的学术研究机构的教员，并进行NIH资助的工作，为 通过阐明抗肿瘤免疫和开发新的免疫疗法，在肿瘤免疫学领域发挥重要作用。

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.