2024
Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity
Zhang T, Yu W, Cheng X, Yeung J, Ahumada V, Norris P, Pearson M, Yang X, van Deursen W, Halcovich C, Nassar A, Vesely M, Zhang Y, Zhang J, Ji L, Flies D, Liu L, Langermann S, LaRochelle W, Humphrey R, Zhao D, Zhang Q, Zhang J, Gu R, Schalper K, Sanmamed M, Chen L. Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity. Science Immunology 2024, 9: eadh2334. PMID: 38669316, DOI: 10.1126/sciimmunol.adh2334.Peer-Reviewed Original ResearchConceptsT cell infiltrationT cell exclusionT cellsResistance to anti-PD-1 immunotherapyPoor T-cell infiltrationAnti-PD-1 immunotherapyImmunogenic mouse tumorsT cell mobilizationHuman cancer tissuesTherapeutic immunotherapyCancer immunotherapyMouse tumorsChemokine systemImmunotherapyTumor tissuesImpaired infiltrationTumorLipid metabolitesHuman cancersCancer tissuesInfiltrationA2 groupCancerPLA2G10Up-regulated
2022
CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary.
Melero I, Sanmamed M, Glez-Vaz J, Luri-Rey C, Wang J, Chen L. CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary. Cancer Discovery 2022, 13: 552-569. PMID: 36576322, DOI: 10.1158/2159-8290.cd-22-1029.Peer-Reviewed Original ResearchConceptsAnti-CD137 monoclonal antibodiesT cell antitumor immunitySevere liver inflammationTolerable safety profileCancer immunotherapy strategiesNatural killer lymphocytesSingle-agent activityNon-Hodgkin lymphomaEarly phase trialsChimeric antigen receptorCD137 agonistsEnhanced CD8Unacceptable toxicityAntitumor immunityLiver inflammationImmunotherapy strategiesSafety profileCancer immunotherapyKiller lymphocytesClinical activityAgonist antibodyPharmacodynamic activityMouse modelCD137Costimulatory receptorsThe CD8α–PILRα interaction maintains CD8+ T cell quiescence
Zheng L, Han X, Yao S, Zhu Y, Klement J, Wu S, Ji L, Zhu G, Cheng X, Tobiasova Z, Yu W, Huang B, Vesely MD, Wang J, Zhang J, Quinlan E, Chen L. The CD8α–PILRα interaction maintains CD8+ T cell quiescence. Science 2022, 376: 996-1001. PMID: 35617401, DOI: 10.1126/science.aaz8658.Peer-Reviewed Original ResearchConceptsT cell quiescenceT cellsT cell pool sizeMaintenance of CD8Peripheral lymphoid organsCell quiescenceMemory CD8Antigen exposureLymphoid organsActivation phenotypeCD8Specific antigenCD8αInducible deletionCell pool sizeDiverse antigensAntigenMolecular mechanismsBroad repertoireExposureCellsQuiescent stateTumorsMicePILRαResistance Mechanisms to Anti-PD Cancer Immunotherapy
Vesely MD, Zhang T, Chen L. Resistance Mechanisms to Anti-PD Cancer Immunotherapy. Annual Review Of Immunology 2022, 40: 45-74. PMID: 35471840, DOI: 10.1146/annurev-immunol-070621-030155.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAnti-PD therapyCancer immunotherapyMechanisms of resistanceImmune inhibitory moleculesFraction of patientsResistance mechanismsNormalization cancer immunotherapyAdditional immunotherapyPD-1Clinical evidenceAntigen presentationT cellsSolid tumorsTherapy resistanceH1 pathwayTumor microenvironmentImmunotherapyInhibitory moleculesHematopoietic malignanciesCancer treatmentTherapyPatientsCurrent studyCancer dataMalignancy
2021
Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy
Sun Y, Chen W, Torphy RJ, Yao S, Zhu G, Lin R, Lugano R, Miller EN, Fujiwara Y, Bian L, Zheng L, Anand S, Gao F, Zhang W, Ferrara SE, Goodspeed AE, Dimberg A, Wang XJ, Edil BH, Barnett CC, Schulick RD, Chen L, Zhu Y. Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy. Science Translational Medicine 2021, 13 PMID: 34321321, PMCID: PMC8749958, DOI: 10.1126/scitranslmed.abc8922.Peer-Reviewed Original ResearchConceptsInsulin-like growth factor binding protein 7Vascular dysfunctionAnti-programmed death-1/Intratumoral effector T cellsTumor vasculatureTumor microenvironmentGrowth factor binding protein 7Tumor-associated endothelial cellsImproved antitumor responsesEffector T cellsDeath-1/Immune checkpoint therapyImmune cell infiltrationFavorable tumor microenvironmentMouse tumor modelsBinding protein 7Checkpoint therapyAntitumor responseCell infiltrationPoor responseT cellsHypoxic tumor microenvironmentTumor perfusionSolid tumorsTherapeutic interventionsA Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy
Sanmamed MF, Nie X, Desai SS, Villaroel-Espindola F, Badri T, Zhao D, Kim AW, Ji L, Zhang T, Quinlan E, Cheng X, Han X, Vesely MD, Nassar AF, Sun J, Zhang Y, Kim TK, Wang J, Melero I, Herbst RS, Schalper KA, Chen L. A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy. Cancer Discovery 2021, 11: 1700-1715. PMID: 33658301, PMCID: PMC9421941, DOI: 10.1158/2159-8290.cd-20-0962.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerTumor-infiltrating lymphocytesExhausted T cellsTIL subsetsTumor microenvironmentCancer immunotherapyT cellsAdvanced non-small cell lung cancerPatient-derived tumor xenograft modelAnti-PD therapyT cell subsetsCell lung cancerPotential tissue biomarkersBaseline tumor tissueLung cancer tissuesSingle-cell mass cytometryTumor xenograft modelApoptotic CD8Dysfunctional CD8Immunotherapy resistancePD-1Activation markersAdjacent nontumoral tissuesPathway-dependent mannerLung cancer
2019
PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus
Han X, Vesely MD, Yang W, Sanmamed MF, Badri T, Alawa J, López-Giráldez F, Gaule P, Lee SW, Zhang JP, Nie X, Nassar A, Boto A, Flies DB, Zheng L, Kim TK, Moeckel GW, McNiff JM, Chen L. PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus. Science Translational Medicine 2019, 11 PMID: 31826980, DOI: 10.1126/scitranslmed.aax1159.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArthritisAutoantibodiesAutoimmunityDendritic CellsHumansInflammationInterferon Type ILupus Erythematosus, CutaneousLupus Erythematosus, SystemicMembrane ProteinsMice, Inbred BALB CMice, Inbred MRL lprMyeloid CellsNeutrophilsReceptors, Antigen, T-CellSignal TransductionTerpenesUp-RegulationConceptsPlasmacytoid dendritic cellsDiscoid lupus erythematosusSystemic lupus erythematosusCutaneous lupus lesionsPD-1HLupus erythematosusLupus lesionsAutoimmune diseasesKO miceT cellsMyeloid cellsHuman systemic lupus erythematosusBALB/c backgroundCutaneous lupus erythematosusInappropriate immune responseProgression of lupusSystemic autoimmune diseaseImmune cell expansionSuppression of autoimmunityAgonistic monoclonal antibodyDeath-1 homologCutaneous lupusProinflammatory neutrophilsDendritic cellsDLE lesionsSiglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, Zhang J, Song C, Zarr M, Zhou X, Han X, Archer KA, O’Neill T, Herbst RS, Boto AN, Sanmamed MF, Langermann S, Rimm DL, Chen L. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nature Medicine 2019, 25: 656-666. PMID: 30833750, PMCID: PMC7175920, DOI: 10.1038/s41591-019-0374-x.Peer-Reviewed Original ResearchConceptsNormalization cancer immunotherapyTumor microenvironmentSiglec-15Antibody blockadeCancer immunotherapyImmune suppressorMyeloid cellsAntigen-specific T cell responsesB7-H1/PDTumor-infiltrating myeloid cellsB7-H1 moleculesAnti-tumor immunityT cell responsesPotential targetImmune evasion mechanismsInhibits tumor growthMacrophage colony-stimulating factorColony-stimulating factorB7-H1Evasion mechanismsMouse modelHuman cancer cellsTumor growthCell responsesGenetic ablation
2018
Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3
Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, Zheng L, Zhou T, Badri T, Yao S, Zhu S, Boto A, Sznol M, Melero I, Vignali DAA, Schalper K, Chen L. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell 2018, 176: 334-347.e12. PMID: 30580966, PMCID: PMC6365968, DOI: 10.1016/j.cell.2018.11.010.Peer-Reviewed Original ResearchConceptsFibrinogen-like protein 1MHC-IILAG-3Major histocompatibility complex class IILymphocyte activation gene-3Histocompatibility complex class IILiver-secreted proteinsImmune inhibitory receptorsProtein 1Immune evasion mechanismsCell immunityTumor immunityPoor prognosisCancer immunotherapyCancer patientsInhibitory receptorsEvasion mechanismsHuman cancer cellsCell activationClass IIMouse tumorsMonoclonal antibodiesCancer cellsInhibitory ligandsInhibitory function