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
基本信息
- 批准号:10504399
- 负责人:
- 金额:$ 58.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAffectAffinityAnimal ModelAntibodiesBindingBinding SitesBiochemicalBiological AssayBiological MarkersBiological ProductsBiologyBlocking AntibodiesBloodBlood CirculationCD4 Positive T LymphocytesCD8B1 geneCancer PatientClinicalClinical TrialsCryoelectron MicroscopyDataDoseEpitopesFibrinogenFosteringFutureGenesGeneticHepatocyteHumanHybridomasImmuneImmunityImmunosuppressionImmunotherapyIn VitroIndividualKRAS oncogenesisKnowledgeLeadLicensingLigandsLiverLung AdenocarcinomaLymphocyteMajor Histocompatibility ComplexMalignant NeoplasmsMapsMediatingModelingMonoclonal AntibodiesMusMutationNivolumabNon-Small-Cell Lung CarcinomaNormal tissue morphologyPD-1/PD-L1Pathway interactionsPatientsPhasePlasmaProteinsResistanceRoentgen RaysRoleSeriesSignal TransductionSumSystemT cell regulationT cell responseT-Cell ActivationT-LymphocyteTestingTherapeuticTimeTissuesTransplantationTumor ImmunityTumor TissueUp-Regulationanti-CTLA4anti-PD-1anti-PD-1/PD-L1antigen-specific T cellsbasecancer cellcancer immunobiologycancer immunotherapycarcinogenesischeckpoint receptorschemokineclinical applicationcohortcytokinedesignexperiencegenome-wideimmune cell checkpointsimmune checkpointimmune checkpoint blockadeimmune functionin vivoinnovationinsightmelanomanext generationnovelnovel strategiespatient biomarkerspatient responsepatient stratificationpredicting responsepredictive markerprognostic valueprogrammed cell death protein 1programsreceptorresponsetumortumor immunologytumor microenvironmenttumor xenograft
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JUN WANG其他文献
JUN WANG的其他文献
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{{ truncateString('JUN WANG', 18)}}的其他基金
Elucidating the Immune Suppressive Mechanism of SIGLEC-15 in the Tumor Microenvironment
阐明 SIGLEC-15 在肿瘤微环境中的免疫抑制机制
- 批准号:
10587743 - 财政年份:2022
- 资助金额:
$ 58.88万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 58.88万 - 项目类别:
Functional characterization of SARS-CoV-2 myeloid cell receptors as an immunopathogenic mechanisms of COVID-19
SARS-CoV-2 骨髓细胞受体作为 COVID-19 免疫致病机制的功能特征
- 批准号:
10288857 - 财政年份:2021
- 资助金额:
$ 58.88万 - 项目类别:
Functional characterization of SARS-CoV-2 myeloid cell receptors as an immunopathogenic mechanisms of COVID-19
SARS-CoV-2 骨髓细胞受体作为 COVID-19 免疫致病机制的功能特征
- 批准号:
10443833 - 财政年份:2021
- 资助金额:
$ 58.88万 - 项目类别:
HIGH RESOLUTION STRUCTURES BY MINIMIZING RADIATION EFFECTS
通过最小化辐射效应实现高分辨率结构
- 批准号:
7721228 - 财政年份:2008
- 资助金额:
$ 58.88万 - 项目类别:
SPECIFIC CHEMICAL INTERACTIONS IN MATRIX-INCORPORATED INSULIN STRUCTURES
基质结合的胰岛素结构中的特定化学相互作用
- 批准号:
7721229 - 财政年份:2008
- 资助金额:
$ 58.88万 - 项目类别:
IMPLICATIONS OF DISULFIDES BREAKING SEQUENCE IN REDUCTIVE UNFOLDING PATHWAYS
二硫化物断裂序列对还原性展开路径的影响
- 批准号:
7721227 - 财政年份:2008
- 资助金额:
$ 58.88万 - 项目类别:
SPECIFIC CHEMICAL INTERACTIONS IN MATRIX-INCORPORATED INSULIN STRUCTURES
基质结合的胰岛素结构中的特定化学相互作用
- 批准号:
7369520 - 财政年份:2005
- 资助金额:
$ 58.88万 - 项目类别:
IMPLICATIONS OF DISULFIDES BREAKING SEQUENCE IN REDUCTIVE UNFOLDING PATHWAYS
二硫化物断裂序列对还原性展开路径的影响
- 批准号:
7369518 - 财政年份:2005
- 资助金额:
$ 58.88万 - 项目类别:
HIGH RESOLUTION STRUCTURES BY MINIMIZING RADIATION EFFECTS
通过最小化辐射效应实现高分辨率结构
- 批准号:
7369519 - 财政年份:2005
- 资助金额:
$ 58.88万 - 项目类别:
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