KIR2DL2 Immune Checkpoint as Modulator of T-Cell Effector Function

KIR2DL2 免疫检查点作为 T 细胞效应器功能的调节器

基本信息

批准号：
10649989
负责人：
Daniel Abate-Daga
金额：
$ 19.69万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649989
关键词：
Ablation Adoptive Immunotherapy Animal Model Autoimmunity Binding Biological Biological Assay Biology CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Death Induction Cells Cellular biology Clinical Clonal Expansion Clustered Regularly Interspaced Short Palindromic Repeats Conditioned Reflex Data Docking Education Elements Event General Population Genes Genetic Genetic Transcription Genomics Goals HLA-C Antigens Human ITIM Immune Immunoglobulins Immunologic Surveillance Immunoprecipitation Immunotherapy Impairment Infusion procedures Interferon Type II Killer Cells Knowledge acquisition Ligands Link Liquid substance Lymphocyte Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Memory Methods Modeling Modification Molecular Molecular Mechanisms of Action Natural Killer Cells Outcome PTPN6 gene Pathway interactions Patient observation Patients Performance Pre-Clinical Model Proteomics Protocols documentation Research Role Shapes Signal Pathway Signal Transduction Solid Solid Neoplasm T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Transgenic Organisms Tyrosine Up-Regulation Virus Diseases Western Blotting Xenograft Model chimeric antigen receptor chimeric antigen receptor T cells cytokine cytotoxic design effector T cell engineered T cells genome editing immune cell checkpoints immune checkpoint improved in vivo killer immunoglobulin-like receptor manufacture melanoma mouse model mutant neoplastic cell novel overexpression pancreatic cancer model pharmacologic prevent receptor receptor binding receptor expression translational potential tumor tumor growth γδ T cells

项目摘要

Project Summary Killer cell immunoglobulin-like receptors (KIR) are mainly expressed by NK cells, although their expression has also been described in CD4+, CD8+ and γδ T cells. Within CD8 T cells, KIR expression is induced at later stages of lymphocyte maturation and is thought to regulate specific T cell effector functions. Within KIR receptors, KIR2DL2 modulates T cell effector functions, as KIR2DL2+ CD8+ T cells present reduced level of activation-induced cell death, and poor IFN-γ secretion after T cell receptor (TCR) stimulation. The notion of a suppressive function of KIR2DL2 expression in CD8+ T cells is supported by the observation that patients that express its cognate ligand, HLA-C1, showed decreased overall survival and could not control tumor growth. Our preliminary data show that KIR2DL2 expression increases in vivo in adoptively transferred T cells in patients and in preclinical models of adoptive immunotherapy. Using a pancreatic tumor model, we found that chimeric antigen receptor (CAR)-T cells expressing KIR2DL2 were significantly less cytotoxic than their KIR2DL2- counterparts in presence of KIR2DL2’s ligand. Furthermore, KIR2DL2 expression in CAR-T cells was associated with reduced antitumor efficacy, in an HLA-I-dependent manner, in a murine model of pancreatic cancer. Based on these preliminary findings we hypothesize that KIR2DL2 behaves as a T cell immune checkpoint, modulating T cell effector function and leading to an ineffective immunosurveillance. Therefore, targeting KIR2DL2 during T cell manufacturing may improve T cell performance after cell infusion. We will test our hypothesis by 1) Defining the modulatory mechanisms whereby KIR2DL2 shapes CAR- and TCR-transgenic T cell antitumoral effector function. We will determine the overall effect of KIR2DL2 engagement in TCR-transgenic and CAR-T cell effector function. Additionally, we will determine which regions within KIR2DL2 are responsible for its modulatory function. Finally, we will characterize both the KIR2DL2 signaling interactome and the downstream events triggered by its ligand interaction by immunoprecipitation and proteomic analyses. 2) Improving T cell performance for the enhancement of adoptive cell immunotherapies (ACTs) by abrogating KIR2DL2 function. To prevent its inhibitory effect, manipulation of KIR2DL2 expression and/or signaling will be conducted and adapted to the current protocols for CAR-T cell manufacturing. Based on the anticipated results, we will link for the first time the biological and molecular function of KIR2DL2 within therapeutic T cells. The proposed studies will increase our mechanistic understanding of KIR2DL2 biology and will generate novel cell products with high translational potential.

项目摘要杀伤细胞免疫球蛋白样受体（KIR）主要由NK细胞表达，尽管它们表达也已在CD4+，CD8+和γδT细胞中描述。在CD8 T细胞中，KIR表达为在淋巴细胞成熟的后期诱导，被认为调节特定T细胞效应子功能。在KIR受体中，KIR2DL2调节T细胞效应子功能，因为Kir2DL2+ CD8+ T细胞存在激活诱导的细胞死亡水平降低，T细胞受体（TCR）后IFN-γ的分泌较差刺激。 CD8+ T细胞中KIR2DL2表达的抑制功能的概念由观察到表达其同源配体HLA-C1的患者表明总体生存率有所提高，并且无法控制肿瘤生长。我们的初步数据表明，Kir2DL2表达在体内增加在患者和适应性免疫疗法的临床前模型中，Typer转移了T细胞。使用胰腺肿瘤模型，我们发现表达Kir2DL2的嵌合抗原受体（CAR）-T细胞为在KIR2DL2配体的存在下，其细胞毒性明显少于其Kir2DL2-对应物。此外， CAR-T细胞中的KiR2DL2表达与HLA-I依赖性的抗肿瘤效率降低有关方式，在胰腺癌的鼠模型中。基于这些初步发现，我们假设 KIR2DL2作为T细胞免疫检查点的行为，调节T细胞效应子功能，并导致无效的免疫监视。因此，针对T细胞制造过程中的KIR2DL2可能输注细胞后提高T细胞性能。我们将通过1）定义调节方法来检验我们的假设 KIR2DL2塑造CAR和TCR-转基因T细胞抗肿瘤效应子功能的机制。我们将确定KIR2DL2参与对TCR-转基因和CAR-T细胞效应子功能的总体效应。此外，我们将确定KIR2DL2中的哪些区域负责其调节功能。最后，我们将表征KIR2DL2信号交互组和触发的下游事件通过免疫沉淀和蛋白质组学分析的配体相互作用。 2）改善T细胞性能通过废除KIR2DL2功能来增强自适应细胞免疫疗法（ACT）。防止它抑制作用，将进行KIR2DL2表达和/或信号传导的操纵并适应 CAR-T细胞制造的当前协议。根据预期的结果，我们将首次链接拟议的研究将提高我们对KIR2DL2生物学的机械理解，并将生成具有较高的新细胞产品翻译潜力。