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Targeting Checkpoint Inhibition in Anti-Tumor Responses

Targeting Checkpoint Inhibition in Anti-Tumor Responses
抗肿瘤反应中针对检查点抑制
批准号:
10372199
负责人:
Linda Mac Pherson Bradley
金额:
$9.75万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-05-01 至 2023-04-30
关键词:
AddressAdoptive TransferAgonistAntitumor ResponseBindingBiological ProductsBlocking AntibodiesCCL19 geneCCL21 geneCD8-Positive T-LymphocytesCTLA4 geneCell Adhesion MoleculesCell physiologyCellsChronicCollaborationsEffectivenessFUS-1 ProteinFab ImmunoglobulinsFamilyGenesGenetic TranscriptionGlycoproteinsGoalsHematopoieticHomologous GeneHumanImmuneImmune checkpoint inhibitorImmune systemImmunosuppressionImmunotherapyIndividualInfectionInflammationLeukocytesLigandsLigationLinkLymphocytic choriomeningitis virusMalignant NeoplasmsMetastatic MelanomaModelingMonoclonal AntibodiesMusMutation AnalysisMyeloid CellsP-SelectinP-selectin ligand proteinPD-1/PD-L1PD-L1 blockadePathway interactionsPatientsPopulation HeterogeneityProductionRecombinantsRegulatory T-LymphocyteRoleSelectinsT cell differentiationT cell responseT-Cell ReceptorT-LymphocyteTestingTherapeutic InterventionToxic effectTreatment EffectivenessTumor ImmunityVirus Diseasesadvanced diseaseanti-PD-1anti-PD1 therapycancer therapycheckpoint inhibitionchemokineclinical translationcytokinecytotoxicityexhaustexhaustionfunctional disabilitygenetic analysishuman monoclonal antibodiesimmune checkpoint blockadeimmunoregulationimprovedin vivolymph nodesmelanomamigrationmouse modelneoantigensnovelnovel therapeuticsoptimismpatient subsetsprogenitorprogrammed cell death ligand 1programmed cell death protein 1receptorreceptor expressionreceptor functionresponsesialyl Lewis xstem-like cellsynergismtargeted treatmenttherapeutic candidatetooltranslational potentialtumortumor eradicationtumor growthtumor microenvironment

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英文摘要
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.
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Targeting Checkpoint Inhibition in Anti-Tumor Responses
Regulation of CD4+ T cell responses during chronic viral infection
Regulation of CD4+ T Cell Responses During Chronic Viral Infection
Frontiers in Fundamental and Translational Immunology
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