Elucidating the Role of Cancer-Associated FGL1 in Tumor Immunity and Developing FGL1-Guided Anti-LAG-3 Cancer Immunotherapy

阐明癌症相关 FGL1 在肿瘤免疫中的作用并开发 FGL1 引导的抗 LAG-3 癌症免疫疗法

• 批准号: 10663382
• 负责人: JUN WANG
• 金额: $ 56万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-11 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663382
• 关键词: Ablation; Activated Lymphocyte; Affect; Affinity; Animal Model; Antibodies; Binding; Binding Sites; Biochemical; Biological Assay; Biological Markers; Biological Products; Biology; Blocking Antibodies; Blood; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Circulation; Clinical; Clinical Trials; Cryoelectron Microscopy; Data; Dose; Epitopes; Fibrinogen; Fostering; Future; Genes; Genetic; Hepatocyte; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Hybridomas; Immune; Immunity; Immunosuppression; Immunotherapy; In Vitro; Individual; KRAS oncogenesis; Knowledge; Lead; Licensing; Ligands; Liver; Lung Adenocarcinoma; Malignant Neoplasms; Maps; Mediating; Modeling; Monoclonal Antibodies; Mus; Mutation; Nivolumab; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; PD-1/PD-L1; Pathway interactions; Patients; Phase II/III Trial; Plasma; Proliferating; Protein Secretion; Proteins; Resistance; Role; Series; Shapes; Signal Transduction; System; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Tumor Immunity; Tumor Tissue; Up-Regulation; X-Ray Crystallography; anti-CTLA4; anti-PD-1; anti-PD-1/PD-L1; antigen-specific T cells; cancer cell; cancer immunobiology; cancer immunotherapy; carcinogenesis; checkpoint receptors; chemokine; clinical application; cohort; cytokine; design; experience; genome-wide; immune cell checkpoints; immune checkpoint; immune checkpoint blockade; immune function; in vivo; innovation; insight; melanoma; next generation; novel; novel strategies; overexpression; patient biomarkers; patient response; patient stratification; predicting response; predictive marker; prognostic value; programmed cell death protein 1; programs; receptor; response; tumor; tumor immunology; tumor microenvironment; tumor xenograft

Project Summary Resistance to anti-CTLA-4, PD-1/PD-L1 (PD) T cell-based immune checkpoint blockade (ICB) therapy in large subsets of cancer patients necessitates the search for other tumor-associated T cell immune checkpoints that critically affect tumor immunity. Lymphocyte activating gene 3 (LAG-3) is a T-cell inhibitory receptor and represents a promising target for cancer immunotherapy, as monoclonal antibodies (mAb) blocking LAG-3 with its known ligand, MHC-II, in combination with anti-PD-1 show modest but promising efficacy in recent clinical trials. The FDA recently accepted for priority review the biologics license application for LAG-3 blocking mAb relatlimab and anti-PD-1 nivolumab fixed-dose combination for treating melanoma. However, very few single- agent activities of these MHC-II blocking anti-LAG-3 mAbs were observed, and no useful biomarkers for patient stratification have been suggested thus far. Motivated by numerous studies suggesting that the immunosuppressive effect of LAG-3 is largely independent of MHC-II, we identified for the first time that fibrinogen-like protein 1 (FGL1) is a high affinity and major functional ligand for LAG-3 whose interaction interface is distinct from MHC-II. FGL1 is a hepatocyte-secreted protein that can be detected in circulation. We found that soluble FGL1 inhibits antigen-specific T cell activation in a LAG-3 dependent manner. FGL1 genetic ablation or antibody blockade in mice promotes anti-tumor immunity in established mouse tumors, even in FGL1 negative tumors, suggesting a functional role of host-derived FGL1. In contrast to its minimal expression in normal tissues except the liver, FGL1 is upregulated by cancer cells in multiple cancers, such as non-small cell lung cancer (NSCLC) and melanoma; however, the role of tumor-associated FGL1 in the control of tumor immunity is still unclear. The major anti-LAG-3 clinical programs currently focus on those blocking only the MHC-II/LAG-3 interaction, which do not elicit any single-agent activities. Thus, it is critical to mechanistically dissect the immunological function of the FGL1/LAG-3 axis in the tumor microenvironment to design better LAG-3 targeted approaches for clinical application. In this project and through two complementary aims, we will leverage our extensive experience and expertise in cancer immunology and immunotherapy to 1) determine the functional role of tumor-associated FGL1 in modulating tumor immunity, its cancer induction mechanism by oncogenic Kras mutations and functional biomarker value in predicting responses to immunotherapies; 2) develop FGL1-guided, next-generation anti-LAG-3 cancer immunotherapy. We will compare the anti-tumor efficacy of our in-house anti- human or mouse LAG-3 antibodies that differentially block either or both FGL1/MHC-II and map the LAG-3 binding interfaces of these antibodies via CryoEM and X-ray crystallographic studies. In sum, our proposed studies will significantly deepen our understanding of the newly defined FGL1/LAG-3 axis and foster new immunotherapy designs for treating human cancers.

项目摘要 大规模研究中对基于抗CTLA-4、PD-1/PD-L1（PD）T细胞的免疫检查点阻断（ICB）疗法的耐药性 癌症患者的亚群需要寻找其他肿瘤相关的T细胞免疫检查点， 严重影响肿瘤免疫。淋巴细胞活化基因3（LAG-3）是T细胞抑制性受体， 代表了癌症免疫治疗的有希望的靶点，因为单克隆抗体（mAb）阻断LAG-3， 其已知配体MHC-II与抗PD-1组合在最近的临床试验中显示出适度但有希望的功效， 审判FDA最近接受了LAG-3阻断mAb的生物制剂许可申请， 在一些实施方案中，本发明提供了用于治疗黑素瘤的雷拉利单抗和抗PD-1纳武单抗固定剂量组合。然而，很少有单身- 观察到这些MHC-II阻断性抗LAG-3 mAb的活性，并且对于患者没有有用的生物标志物。 到目前为止已经提出了分层。许多研究表明， LAG-3的免疫抑制作用在很大程度上不依赖于MHC-II，我们首次鉴定出， 纤维蛋白原样蛋白1（FGL 1）是LAG-3的高亲和力和主要功能配体，其相互作用界面是 不同于MHC-II。FGL 1是一种肝细胞分泌的蛋白质，可在循环中检测到。我们发现 可溶性FGL 1以LAG-3依赖性方式抑制抗原特异性T细胞活化。FGL 1基因消融或 小鼠中的抗体阻断促进了已建立的小鼠肿瘤中的抗肿瘤免疫，即使在FGL 1阴性小鼠中也是如此。 肿瘤，表明宿主来源的FGL 1的功能作用。与其在正常组织中的最低表达相反， 除肝脏外，FGL 1在多种癌症中被癌细胞上调，例如非小细胞肺癌 然而，肿瘤相关的FGL 1在控制肿瘤免疫中的作用仍然是未知的。 不清楚目前主要的抗LAG-3临床项目集中在仅阻断MHC-II/LAG-3的那些 交互，不引起任何单一代理活动。因此，关键是要机械地剖析 FGL 1/LAG-3轴在肿瘤微环境中的免疫功能，以设计更好的LAG-3靶向 临床应用的方法。在这个项目中，通过两个互补的目标，我们将利用我们的 在癌症免疫学和免疫治疗方面的丰富经验和专业知识，以1）确定功能作用 肿瘤相关FGL 1在调节肿瘤免疫中的作用及其致癌Kras的致癌机制 突变和功能性生物标志物在预测对免疫疗法的应答中的价值; 2）开发FGL 1指导的， 下一代抗LAG-3癌症免疫疗法我们将比较我们的内部抗肿瘤药物的抗肿瘤效果， 差异性阻断FGL 1/MHC-II之一或两者并定位LAG-3的人或小鼠LAG-3抗体 通过CryoEM和X射线晶体学研究这些抗体的结合界面。总而言之，我们的建议 研究将大大加深我们对新定义的FGL 1/LAG-3轴的理解，并促进新的 用于治疗人类癌症的免疫疗法设计。