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: 10504399
• 负责人: JUN WANG
• 金额: $ 58.88万
• 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/10504399
• 关键词: Ablation; 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; Clinical; Clinical Trials; Cryoelectron Microscopy; Data; Dose; Epitopes; Fibrinogen; Fostering; Future; Genes; Genetic; Hepatocyte; Human; Hybridomas; Immune; Immunity; Immunosuppression; Immunotherapy; In Vitro; Individual; KRAS oncogenesis; Knowledge; Lead; Licensing; Ligands; Liver; Lung Adenocarcinoma; Lymphocyte; Major Histocompatibility Complex; 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; Plasma; Proteins; Resistance; Roentgen Rays; Role; Series; Signal Transduction; Sum; System; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Tumor Immunity; Tumor Tissue; Up-Regulation; anti-CTLA4; anti-PD-1; anti-PD-1/PD-L1; antigen-specific T cells; base; 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; 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.

项目总结