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Targeting Checkpoint Inhibition in Anti-Tumor Responses

抗肿瘤反应中针对检查点抑制

基本信息

批准号：
10202111
负责人：
Linda Mac Pherson Bradley
金额：
$ 9.75万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202111
关键词：
Address Adoptive Transfer Agonist Antitumor Response Binding Biological Blocking Antibodies CCL19 gene CCL21 gene CD8-Positive T-Lymphocytes CTLA4 gene Cell Adhesion Molecules Cell physiology Cells Chronic Collaborations Effectiveness FUS-1 Protein Fab Immunoglobulins Family Genes Genetic Transcription Glycoproteins Goals Hematopoietic Homologous Gene Human Immune Immune checkpoint inhibitor Immune system Immunosuppression Immunotherapy Individual Infection Inflammation Leukocytes Ligands Ligation Link Lymphocytic choriomeningitis virus Malignant Neoplasms Metastatic Melanoma Modeling Monoclonal Antibodies Mus Mutation Analysis Myeloid Cells P-Selectin P-selectin ligand protein PD-1/PD-L1 PD-L1 blockade Pathway interactions Patients Population Heterogeneity Production Recombinants Regulatory T-Lymphocyte Role Selectins T cell differentiation T cell response T-Cell Receptor T-Lymphocyte Testing Therapeutic Intervention Toxic effect Treatment Effectiveness Tumor Immunity Virus Diseases advanced disease anti-PD-1 anti-PD1 therapy cancer therapy checkpoint inhibition chemokine clinical translation cytokine cytotoxicity exhaust exhaustion functional disability genetic analysis human monoclonal antibodies immune checkpoint blockade immunoregulation improved in vivo lymph nodes melanoma migration mouse model neoantigens novel novel therapeutics optimism patient subsets progenitor programmed cell death ligand 1 programmed cell death protein 1 receptor receptor expression receptor function response sialyl Lewis x stem-like cell synergism targeted treatment therapeutic candidate tool tumor tumor eradication tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY The goal of this project is to evaluate novel therapeutics that block PSGL-1 (P-selectin glycoprotein-1), which we identified as a key inhibitory receptor (IR) that is expressed on T cells, and address the impact(s) on immune cell functions in the tumor microenvironment (TME). PSGL-1 is a conserved ligand for the selectin family of adhesion molecules, P, E, and L, that is expressed on most hematopoietic cells and regulates leukocyte migration when fully glycosylated. T cells are the only cells that express the non-selectin binding form of PSGL- 1 that serves as a receptor for the lymph node chemokines, CCL19 and CCL21, and the PD-L1 homologue, VISTA (B7-H5). We showed that PSGL-1-deficient (Selplg-/-) CD8 T cells fail to acquire the hallmarks of exhaustion compared to their wild-type (WT) counterparts after infection with chronic lymphocytic choriomeningitis virus and significantly limit tumor growth in two murine models of melanoma, one that is nonresponsive to anti-PD-1 treatment. We identified that TILs from Selplg-/- mice have greater anti-tumor function, including cytotoxicity and cytokine production. Moreover, expression of multiple inhibitory receptors (IRs) that distinguish exhausted T cells (TEX) were downregulated on Selplg-/- T cells, including PD-1, BTLA, CD160, LAG3, and TIM3. Notably, PSGL-1 ligation on naïve T cells (TN) and TEX by an agonist mAb in the context of T cell receptor stimulation induced/augmented expression of multiple IRs, underscoring an integral connection of PSGL-1 to immune inhibitory pathways and suggesting a link to the recently identified inhibitory gene module that regulates the coordinated transcription of IRs. We identified that a monovalent Fab of the same agonist mAb dramatically improved T cell responses as did treatment with a rPSGL-1 fusion protein, indicating a capacity to block PSGL-1 function. Notably, blocking PSGL-1 did not lead to widespread inflammation or toxicity. We hypothesize that PSGL-1 blockade has the potential to augment anti-tumor T cell responses by limiting expression levels of multiple IRs, and alter immunosuppression in the TME by impacting other immune cells. We propose to evaluate the effects of PSGL-1 blockade on mouse and human T cell anti-tumor responses using rPSGL-1 and Fab anti-PSGL-1 as comparators to novel mouse and human anti-PSGL-1 blocking mAbs. With these tools, we will analyze the impacts of blocking PSGL-1 on IR expression and functions of T cells and immune cells in the TME, as well as potential synergy with anti-PD-1. In the context of these studies, we will assess the role of VISTA as the relevant PSGL-1 ligand in the TME. These studies will address the potential of targeting PSGL-1 for reversal of T cell exhaustion, induction of anti-tumor immunity, and translational potential.

项目概要该项目的目标是评估阻断 PSGL-1（P-选择素糖蛋白-1）的新型疗法，该疗法我们确定了 T 细胞上表达的关键抑制性受体 (IR)，并解决了对 T 细胞的影响免疫细胞在肿瘤微环境（TME）中发挥作用。 PSGL-1 是选择蛋白的保守配体粘附分子家族 P、E 和 L，在大多数造血细胞上表达并调节白细胞完全糖基化时迁移。 T 细胞是唯一表达 PSGL-非选择素结合形式的细胞 1 作为淋巴结趋化因子 CCL19 和 CCL21 以及 PD-L1 同源物的受体，远景 (B7-H5)。我们发现 PSGL-1 缺陷型 (Selplg-/-) CD8 T 细胞无法获得慢性淋巴细胞感染后与野生型 (WT) 对应物相比，疲劳脉络膜脑膜炎病毒并显着限制两种黑色素瘤小鼠模型中的肿瘤生长，其中一种是对抗 PD-1 治疗无反应。我们发现 Selplg-/- 小鼠的 TIL 具有更强的抗肿瘤作用功能，包括细胞毒性和细胞因子的产生。此外，多种抑制性受体的表达区分衰竭 T 细胞 (TEX) 的 (IR) 在 Selplg-/- T 细胞上下调，包括 PD-1、BTLA、 CD160、LAG3 和 TIM3。值得注意的是，PSGL-1 通过激动剂 mAb 在幼稚 T 细胞 (TN) 和 TEX 上连接 T 细胞受体刺激诱导/增强多种 IR 的表达，强调了整体联系 PSGL-1 与免疫抑制途径的关系，并表明与最近发现的抑制基因模块的联系调节 IR 的协调转录。我们鉴定出相同激动剂 mAb 的单价 Fab 与 rPSGL-1 融合蛋白治疗一样，T 细胞反应得到显着改善，表明有能力阻止 PSGL-1 功能。值得注意的是，阻断 PSGL-1 不会导致广泛的炎症或毒性。我们假设 PSGL-1 阻断有可能通过限制多种 IR 的表达水平，并通过影响其他免疫来改变 TME 中的免疫抑制细胞。我们建议评估 PSGL-1 阻断对小鼠和人类 T 细胞抗肿瘤反应的影响使用 rPSGL-1 和 Fab 抗 PSGL-1 作为新型小鼠和人抗 PSGL-1 阻断单克隆抗体的比较。利用这些工具，我们将分析阻断 PSGL-1 对 IR 表达和 T 细胞功能的影响， TME 中的免疫细胞，以及与抗 PD-1 的潜在协同作用。在这些研究的背景下，我们将评估 VISTA 作为 TME 中相关 PSGL-1 配体的作用。这些研究将解决以下问题的潜力：靶向 PSGL-1 以逆转 T 细胞耗竭、诱导抗肿瘤免疫和转化潜力。