2023
Structural basis for translation inhibition by MERS-CoV Nsp1 reveals a conserved mechanism for betacoronaviruses
Devarkar S, Vetick M, Balaji S, Lomakin I, Yang L, Jin D, Gilbert W, Chen S, Xiong Y. Structural basis for translation inhibition by MERS-CoV Nsp1 reveals a conserved mechanism for betacoronaviruses. Cell Reports 2023, 42: 113156. PMID: 37733586, DOI: 10.1016/j.celrep.2023.113156.Peer-Reviewed Original ResearchConceptsMERS-CoV nsp1Translation inhibitionRibosomal subunitΒ-CoVsModest sequence conservationMRNA entry channelEssential pathogenicity factorHost gene expressionHuman 40S ribosomal subunitSARS-CoV-2 nsp1Cryogenic electron microscopySequence conservationNon-structural protein 1Terminal domainPathogenicity factorsStructural basisGene expressionDevelopment of antiviralsNSP1Entry channelProtein 1Potential therapeutic targetSubunitsExtensive interactionsTherapeutic targetFunction and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
Ren P, Hu Y, Peng L, Yang L, Suzuki K, Fang Z, Bai M, Zhou L, Feng Y, Zou Y, Xiong Y, Chen S. Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages. Signal Transduction And Targeted Therapy 2023, 8: 281. PMID: 37518189, PMCID: PMC10387464, DOI: 10.1038/s41392-023-01509-1.Peer-Reviewed Original ResearchApplications of CRISPR technology in cellular immunotherapy
Zhou X, Renauer P, Zhou L, Fang S, Chen S. Applications of CRISPR technology in cellular immunotherapy. Immunological Reviews 2023, 320: 199-216. PMID: 37449673, PMCID: PMC10787818, DOI: 10.1111/imr.13241.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsImmunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function.
Renauer P, Park J, Bai M, Acosta A, Lee W, Lin G, Zhang Y, Dai X, Wang G, Errami Y, Wu T, Clark P, Ye L, Yang Q, Chen S. Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function. Cancer Immunology Research 2023, 11: 1068-1084. PMID: 37253111, PMCID: PMC10527769, DOI: 10.1158/2326-6066.cir-22-0565.Peer-Reviewed Original ResearchConceptsCAR T cellsHER2-specific CAR T cellsT cellsTumor microenvironmentChimeric antigen receptor T cellsT cell-based immunotherapyAntigen receptor T cellsCD19-specific chimeric antigen receptor (CAR) T cellsCAR T-cell therapyCell-based immunotherapyReceptor T cellsT-cell therapyVivo colorectal cancer modelsColorectal cancer modelT cell functionT cell metabolismTumor infiltrationEvasion mechanismsImmunosuppressive metaboliteImmune evasionCancer modelImmunologic analysisCD19-specificUnfavorable tumor microenvironmentPDK1 deficiencyMassively parallel knock-in engineering of human T cells
Dai X, Park J, Du Y, Na Z, Lam S, Chow R, Renauer P, Gu J, Xin S, Chu Z, Liao C, Clark P, Zhao H, Slavoff S, Chen S. Massively parallel knock-in engineering of human T cells. Nature Biotechnology 2023, 41: 1239-1255. PMID: 36702900, PMCID: PMC11260498, DOI: 10.1038/s41587-022-01639-x.Peer-Reviewed Original ResearchMachine learning identifies T cell receptor repertoire signatures associated with COVID-19 severity
Park J, Lee K, Lam S, Moon K, Fang Z, Chen S. Machine learning identifies T cell receptor repertoire signatures associated with COVID-19 severity. Communications Biology 2023, 6: 76. PMID: 36670287, PMCID: PMC9853487, DOI: 10.1038/s42003-023-04447-4.Peer-Reviewed Original ResearchConceptsCOVID-19 disease severityT cell effector functionT cell receptor repertoireT cell clonal expansionT cell adaptive immune responsesCell effector functionsCOVID-19 patientsTCR repertoire analysisAdaptive immune responsesCell receptor repertoireCOVID-19 severityCOVID-19 infectionCell clonal expansionNF-kB signalingSARS-CoV-2TCR repertoireHealthy donorsImmune responseAntiviral immunityEffector functionsViral infectionHost responseDisease severityReceptor repertoireTCR sequencesRAMIHM generates fully human monoclonal antibodies by rapid mRNA immunization of humanized mice and BCR-seq
Ren P, Peng L, Yang L, Suzuki K, Fang Z, Renauer P, Lin Q, Bai M, Li T, Clark P, Klein D, Chen S. RAMIHM generates fully human monoclonal antibodies by rapid mRNA immunization of humanized mice and BCR-seq. Cell Chemical Biology 2023, 30: 85-96.e6. PMID: 36640761, PMCID: PMC9868106, DOI: 10.1016/j.chembiol.2022.12.005.Peer-Reviewed Original ResearchConceptsHuman monoclonal antibodyHumanized miceMonoclonal antibodiesMemory B cell populationsHumanized transgenic miceBroad antibody responseB cell populationsG protein-coupled receptor targetsNeutralizing antibodiesPeripheral bloodAntibody responseImmunotherapy targetClinical vaccinesPlasma BCell sequencingTransgenic miceImmunization methodReceptor targetsAntibodiesMiceCell populationsHigh potencyImmunizationHigh rateAntibody discovery
2022
Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
Park J, Codina A, Ye L, Lam S, Guo J, Clark P, Zhou X, Peng L, Chen S. Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity. Journal Of Hematology & Oncology 2022, 15: 172. PMID: 36456981, PMCID: PMC9716677, DOI: 10.1186/s13045-022-01389-y.Peer-Reviewed Original ResearchConceptsT cell cytotoxicityCell cytotoxicityT cell killingTumor suppressorCancer patientsImmune responseAvailable agentsSurvival analysisClinical patientsCancer treatmentCancer cellsCancer resistanceDirect targetingPotential new conceptCancer mutationsPatientsCell killingNormal samplesResistance pathwaysCellular responsesSuch resistanceCytotoxicityResistance genesLRRC15 inhibits SARS-CoV-2 cellular entry in trans
Song J, Chow RD, Peña-Hernández MA, Zhang L, Loeb SA, So EY, Liang OD, Ren P, Chen S, Wilen CB, Lee S. LRRC15 inhibits SARS-CoV-2 cellular entry in trans. PLOS Biology 2022, 20: e3001805. PMID: 36228039, PMCID: PMC9595563, DOI: 10.1371/journal.pbio.3001805.Peer-Reviewed Original ResearchConceptsExpression of LRRC15Receptor-binding domainViral entryAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSARS-CoV-2 cellular entrySyndrome coronavirus 2 infectionSARS-CoV-2 entrySpike-mediated entryCoronavirus 2 infectionCOVID-19 patientsCellular entry factorsSARS-CoV-2Attachment factorsACE2-negative cellsEnzyme 2Receptor angiotensinEntry factorsProtective roleLRRC15Spike proteinSame cell typeCRISPR activation screensACE2Cellular entryGenome Engineering for Next-Generation Cellular Immunotherapies
Park JJ, Lee KAV, Lam SZ, Tang K, Chen S. Genome Engineering for Next-Generation Cellular Immunotherapies. Biochemistry 2022, 62: 3455-3464. PMID: 35930700, PMCID: PMC11320893, DOI: 10.1021/acs.biochem.2c00340.Peer-Reviewed Original ResearchConceptsGenome engineeringCellular immunotherapySynthetic biology approachesKnockout of genesGenome engineering approachesGenetic screening approachCell therapyNK cell therapyCAR-NK cellsBiology approachHost-graft interactionsNovel target discoveryLong-term persistenceImmune cell typesCRISPR-CasFuture therapeutic developmentTarget discoveryGenetic modificationCell typesAllogeneic contextTumor effectMultiplexed LNP-mRNA vaccination against pathogenic coronavirus species
Peng L, Fang Z, Renauer PA, McNamara A, Park JJ, Lin Q, Zhou X, Dong MB, Zhu B, Zhao H, Wilen CB, Chen S. Multiplexed LNP-mRNA vaccination against pathogenic coronavirus species. Cell Reports 2022, 40: 111160. PMID: 35921835, PMCID: PMC9294034, DOI: 10.1016/j.celrep.2022.111160.Peer-Reviewed Original ResearchConceptsAntibody responseCoronavirus speciesSequential vaccinationSARS-CoVAntigen-specific antibody responsesSARS-CoV-2 DeltaAdaptive immune cellsEffective immune responsePotent antibody responsesCOVID-19 vaccineSARS-CoV-2MRNA vaccine candidatesActivated B cellsSingle-cell RNA sequencing profilesRNA sequencing profilesSimultaneous vaccinationAntibody immunityVaccination scheduleImmune profileImmune cellsImmune responseVaccine candidatesMERS-CoV.Animal modelsB cellsDevelopment of an efficient reproducible cell-cell transmission assay for rapid quantification of SARS-CoV-2 spike interaction with hACE2
Ssenyange G, Kerfoot M, Zhao M, Farhadian S, Chen S, Peng L, Ren P, Dela Cruz CS, Gupta S, Sutton RE. Development of an efficient reproducible cell-cell transmission assay for rapid quantification of SARS-CoV-2 spike interaction with hACE2. Cell Reports Methods 2022, 2: 100252. PMID: 35757815, PMCID: PMC9213030, DOI: 10.1016/j.crmeth.2022.100252.Peer-Reviewed Original ResearchConceptsAnti-spike monoclonal antibodiesTransmission assaysTherapeutic antiviral drugsSARS-CoV-2Quantitative readoutVirus-cell bindingRapid quantificationConvalescent seraNeutralization assaysAntiviral drugsResearch reagentsSmall molecule drugsClinical settingViral replicationPseudotyped particlesMonoclonal antibodiesLaboratory equipmentQuantitative assayVariant-specific vaccination induces systems immune responses and potent in vivo protection against SARS-CoV-2
Peng L, Renauer PA, Ökten A, Fang Z, Park JJ, Zhou X, Lin Q, Dong MB, Filler R, Xiong Q, Clark P, Lin C, Wilen CB, Chen S. Variant-specific vaccination induces systems immune responses and potent in vivo protection against SARS-CoV-2. Cell Reports Medicine 2022, 3: 100634. PMID: 35561673, PMCID: PMC9040489, DOI: 10.1016/j.xcrm.2022.100634.Peer-Reviewed Original ResearchConceptsImmune responseImmune cell populationsSARS-CoV-2 spikeAssessment of efficacySARS-CoV-2LNP-mRNABreakthrough infectionsCD8 TImmune profilingMRNA vaccinesPotent protectionT lymphocytesNeutralization activityDelta variantAnimal modelsPotent antibodiesRepertoire diversityCell responsesAuthentic virusSystemic increaseVariant lineagesClonal expansionCell populationsCOVID-19VaccinationA genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy
Ye L, Park JJ, Peng L, Yang Q, Chow RD, Dong MB, Lam SZ, Guo J, Tang E, Zhang Y, Wang G, Dai X, Du Y, Kim HR, Cao H, Errami Y, Clark P, Bersenev A, Montgomery RR, Chen S. A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy. Cell Metabolism 2022, 34: 595-614.e14. PMID: 35276062, PMCID: PMC8986623, DOI: 10.1016/j.cmet.2022.02.009.Peer-Reviewed Original ResearchConceptsCAR T cellsT cell-based immunotherapyRight molecular targetCell-based immunotherapyCAR-T therapyChimeric antigen receptorMultiple cancer modelsCAR-T efficacyFunction CRISPR screensCD8 TPrimary CD8Immune functionImmunological diseasesImmune boosterCancer modelAntigen receptorDistinct gene expressionMolecular targetsCRISPR activation screensMetabolic programsImmunological analysisTherapyCancerEfficacyActivation screensHigh-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells
Chen JS, Chow RD, Song E, Mao T, Israelow B, Kamath K, Bozekowski J, Haynes WA, Filler RB, Menasche BL, Wei J, Alfajaro MM, Song W, Peng L, Carter L, Weinstein JS, Gowthaman U, Chen S, Craft J, Shon JC, Iwasaki A, Wilen CB, Eisenbarth SC. High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells. Science Immunology 2022, 7: eabl5652. PMID: 34914544, PMCID: PMC8977051, DOI: 10.1126/sciimmunol.abl5652.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionSARS-CoV-2Follicular helper cellsB cell responsesHelper cellsAntibody productionCell responsesSARS-CoV-2 vaccinationB-cell receptor sequencingSevere COVID-19Cell receptor sequencingIndependent antibodiesT cell-B cell interactionsViral inflammationAntiviral antibodiesImmunoglobulin class switchingVirus infectionGerminal centersViral infectionClonal repertoireInfectionAntibodiesClass switchingCOVID-19Patients
2021
Tumor immunology CRISPR screening: present, past, and future
Dong MB, Tang K, Zhou X, Zhou JJ, Chen S. Tumor immunology CRISPR screening: present, past, and future. Trends In Cancer 2021, 8: 210-225. PMID: 34920978, PMCID: PMC8854335, DOI: 10.1016/j.trecan.2021.11.009.Peer-Reviewed Original ResearchSingle-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes
Ravindra NG, Alfajaro MM, Gasque V, Huston NC, Wan H, Szigeti-Buck K, Yasumoto Y, Greaney AM, Habet V, Chow RD, Chen JS, Wei J, Filler RB, Wang B, Wang G, Niklason LE, Montgomery RR, Eisenbarth SC, Chen S, Williams A, Iwasaki A, Horvath TL, Foxman EF, Pierce RW, Pyle AM, van Dijk D, Wilen CB. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes. PLOS Biology 2021, 19: e3001143. PMID: 33730024, PMCID: PMC8007021, DOI: 10.1371/journal.pbio.3001143.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionSARS-CoV-2Human bronchial epithelial cellsInterferon-stimulated genesCell state changesAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionCell tropismCoronavirus 2 infectionCoronavirus disease 2019Onset of infectionCell-intrinsic expressionCourse of infectionAir-liquid interface culturesHost-viral interactionsBronchial epithelial cellsSingle-cell RNA sequencingCell typesIL-1Disease 2019Human airwaysDevelopment of therapeuticsDrug AdministrationViral replicationThe aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2
Chow RD, Majety M, Chen S. The aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2. Nature Communications 2021, 12: 4. PMID: 33397975, PMCID: PMC7782551, DOI: 10.1038/s41467-020-20323-9.Peer-Reviewed Original ResearchConceptsSARS-CoV-2SARS-CoV-2 infectionHuman lungCOVID-19Natural killer/T-cellAirway smooth muscle cellsSevere coronavirus diseaseSevere COVID-19Alveolar type 2 cellsMajor risk factorType 2 cellsSmooth muscle cellsSARS-CoV-2 proteomeAge-associated genesAge-associated changesDendritic cellsRisk factorsT cellsGoblet cellsAlveolar fibroblastsCoronavirus diseaseMuscle cellsOlder populationCellular landscapeEndothelial cells
2020
CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
Wang G, Chow RD, Zhu L, Bai Z, Ye L, Zhang F, Renauer PA, Dong MB, Dai X, Zhang X, Du Y, Cheng Y, Niu L, Chu Z, Kim K, Liao C, Clark P, Errami Y, Chen S. CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade. Cancer Discovery 2020, 10: 1912-1933. PMID: 32887696, PMCID: PMC7710536, DOI: 10.1158/2159-8290.cd-19-1448.Peer-Reviewed Original ResearchConceptsImmune checkpoint blockadeCheckpoint blockadeCancer typesMajority of patientsRemarkable clinical efficacyFraction of patientsMajor modulatorComplex molecular landscapeMultiple cancer typesClinical efficacyICB responseImmune infiltrationTumor immunogenicityAntigen presentationMutation burdenMouse modelPatient stratificationMutant tumorsTumor microenvironmentIssue featurePatientsTumorsMolecular landscapeBlockadeCancerNonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA
Yuan S, Peng L, Park JJ, Hu Y, Devarkar SC, Dong MB, Shen Q, Wu S, Chen S, Lomakin IB, Xiong Y. Nonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA. Molecular Cell 2020, 80: 1055-1066.e6. PMID: 33188728, PMCID: PMC7833686, DOI: 10.1016/j.molcel.2020.10.034.Peer-Reviewed Original ResearchConceptsInternal ribosome entry site RNANonstructural protein 1Host protein synthesis machineryMRNA entry channelProtein synthesis machineryCryo-EM structureProtein 1Major pathogenicity factorsDifferential expression analysisMRNA-seq dataCellular transcriptomePreinitiation complexSynthesis machineryHuman lung originTranslation inhibitionPathogenicity factorsExpression analysisSite RNAHost viabilityNSP1Protein synthesisEntry channelViral proteinsUnknown mechanismViral RNA