2025
Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism
Steiner K, Young A, Patterson A, Sugiura A, Watson M, Preston S, Zhelonkin A, Jennings E, Chi C, Heintzman D, Pahnke A, Toudji Y, Hatem Z, Madden M, Arner E, Sewell A, Blount A, Okparaugo R, Fallman E, Krystofiak E, Sheldon R, Gibson-Corley K, Voss K, Nowinski S, Jones R, Mogilenko D, Rathmell J. Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism. The Journal Of Immunology 2025, 214: 958-976. PMID: 40204636, PMCID: PMC12123211, DOI: 10.1093/jimmun/vkaf034.Peer-Reviewed Original ResearchConceptsT cell subsetsCD4+ T cell subsetsMitochondrial fatty acid synthesisT cell functionT cellsFatty acid synthesisDecreased mitochondrial respirationTricarboxylic acid intermediatesLipid metabolism genesT cell fateSensitivity to ferroptosisIncreased cell deathCD4+ T cell functionCD8+ T cell numbersCD4+ T cell proliferationMitochondrial stressMetabolic genesCD4+ T cellsCRISPR/Cas9 screenMitochondrial respirationModel of inflammatory bowel diseaseAcid synthesisFitness disadvantageMemory T cellsT cell numbersDEVELOPMENT OF EX VIVO PATIENT-DERIVED MODELS TO UNCOVER THE TUMOR-IMMUNE MICROENVIRONMENT IN RENAL CELL CARCINOMA
Kashima S, Gupta R, Moritz V, Sadak K, Walker J, Adeniran A, Humphrey P, Dinulescu D, Palmer D, Hammond S, Bosenberg M, Hurwitz M, Kenney P, Braun D. DEVELOPMENT OF EX VIVO PATIENT-DERIVED MODELS TO UNCOVER THE TUMOR-IMMUNE MICROENVIRONMENT IN RENAL CELL CARCINOMA. Urologic Oncology Seminars And Original Investigations 2025, 43: 22-23. DOI: 10.1016/j.urolonc.2024.12.057.Peer-Reviewed Original ResearchRCC tumor microenvironmentPatient-derived tumor modelsRenal cell carcinomaImmune checkpoint inhibitorsT cell functionTumor microenvironmentT cellsEnzyme-linked immunosorbent assayFlow cytometryTumor fragmentsTumor samplesCytokine productionImpact of immune checkpoint inhibitorsAnti-PD-1 monoclonal antibodyCD4+CD25+ regulatory T cellsResection of renal cell carcinomaSurgical resection of renal cell carcinomaCD8+ T cell populationsAnti-PD-1 antibodyMetastatic renal cell carcinomaCD20+ B cellsActivated CD8 T cellsEvaluate T cell activationT cell cytokine productionStudy of renal cell carcinomaSafety and Antitumor Activity of a Novel aCD25 Treg Depleter RG6292 as a Single Agent and in Combination with Atezolizumab in Patients with Solid Tumors
Gambardella V, Ong M, Rodriguez-Ruiz M, Machiels J, Sanmamed M, Galvao V, Spreafico A, Renouf D, Luen S, Galot R, de Spéville B, Calvo E, Naing A, Curdt S, Kolben T, Rossmann E, Tanos T, Smart K, Amann M, Xie Y, Xu L, Alcaide E, Städler N, Justies N, Boetsch C, Karanikas V, Schnetzler G, Rohrberg K. Safety and Antitumor Activity of a Novel aCD25 Treg Depleter RG6292 as a Single Agent and in Combination with Atezolizumab in Patients with Solid Tumors. Cancer Research Communications 2025, 5: 422-432. PMID: 39983024, PMCID: PMC11891644, DOI: 10.1158/2767-9764.crc-24-0638.Peer-Reviewed Original ResearchConceptsRecommended phase II dosePhase II doseMaximum tolerated dosePhase I studyTreg depletionSolid tumorsII doseTolerated doseResistance to cancer immunotherapyRegulatory T-cell depletionImmunosuppressive regulatory T cellsEffector T cell functionAdvanced solid tumorsT-cell depletionRegulatory T cellsAnti-CD25 antibodyFrequent adverse eventsT cell functionDose-dependent depletionIL-2 signalingAtezolizumab combinationDeplete TregsTreg reductionDose escalationPeripheral TregsDissecting the role of CAR signaling architectures on T cell activation and persistence using pooled screens and single-cell sequencing
Castellanos-Rueda R, Wang K, Forster J, Driessen A, Frank J, Martínez M, Reddy S. Dissecting the role of CAR signaling architectures on T cell activation and persistence using pooled screens and single-cell sequencing. Science Advances 2025, 11: eadp4008. PMID: 39951542, PMCID: PMC11827634, DOI: 10.1126/sciadv.adp4008.Peer-Reviewed Original ResearchConceptsChimeric antigen receptorT-cell phenotypeT cell responsesT cell activationCAR T cell phenotypesCAR T-cell biologyModulate T cell responsesT cell persistenceCAR-T therapySingle-cell sequencingT cell functionT cell biologyCorrelated in vitroT therapyT cellsAntigen receptorClinical outcomesCD40 costimulationCancer treatmentPhenotypeSignaling domainMembrane-proximal domainCostimulationCD40Screening approachDecreased T helper 1 cell function underlies recurrent sinopulmonary infections in the 17q12 deletion syndrome
Shin J, Shin H, Gutierrez A, Yoo N, Par-Young J, Osmani L, Shin M, Sanchez-Lara P, Bucala R, Soffer G, Kang I. Decreased T helper 1 cell function underlies recurrent sinopulmonary infections in the 17q12 deletion syndrome. EBioMedicine 2025, 112: 105578. PMID: 39891996, PMCID: PMC11840234, DOI: 10.1016/j.ebiom.2025.105578.Peer-Reviewed Original ResearchConceptsCD4<sup>+</sup> T cellsRecurrent sinopulmonary infectionsT cell functionRNA-seq analysisT cellsHealthy controlsSinopulmonary infectionsRNA-seqT-betIFN-gFrequency of CD4<sup>+</sup> T cellsCD4<sup>+</sup> T cell functionTh1 transcription factor T-betDeletion syndromeFlow cytometryCompared to age-matched healthy controlsTranscription factor T-betDecreased T-betUrinary tract abnormalitiesAge-matched healthy controlsMultiplex assayDownstream effector cytokinesEffector cytokinesRecurrent infectionsTh17 cytokinesBile acid synthesis impedes tumor-specific T cell responses during liver cancer
Varanasi S, Chen D, Liu Y, Johnson M, Miller C, Ganguly S, Lande K, LaPorta M, Hoffmann F, Mann T, Teneche M, Casillas E, Mangalhara K, Mathew V, Sun M, Jensen I, Farsakoglu Y, Chen T, Parisi B, Deota S, Havas A, Lee J, Chung H, Schietinger A, Panda S, Williams A, Farber D, Dhar D, Adams P, Feng G, Shadel G, Sundrud M, Kaech S. Bile acid synthesis impedes tumor-specific T cell responses during liver cancer. Science 2025, 387: 192-201. PMID: 39787217, PMCID: PMC12166762, DOI: 10.1126/science.adl4100.Peer-Reviewed Original ResearchMeSH KeywordsAcyltransferasesAnimalsBile Acids and SaltsCarcinoma, HepatocellularCD8-Positive T-LymphocytesCell Line, TumorEndoplasmic Reticulum StressHepatocytesHumansImmune Checkpoint InhibitorsImmunotherapyLithocholic AcidLiver NeoplasmsMiceOxidative StressProgrammed Cell Death 1 ReceptorTumor MicroenvironmentUrsodeoxycholic AcidConceptsTumor-specific T-cell responsesT cell responsesAnti-programmed cell death protein 1Ursodeoxycholic acidCell death protein 1CD8<sup>+</sup> T cellsBile acidsFeatures of human hepatocellular carcinomaImprove tumor immunotherapyInfluence antitumor immunityT cell functionReduced tumor growthBA synthesisLiver cancer modelCancer model systemsHuman hepatocellular carcinomaLandscape of cancerAntitumor immunityTumor immunotherapySecondary bile acidsOrgan-specific metabolitesEndoplasmic reticulum stressT cellsCancer modelsDietary intake
2024
Carbohydrate-Lectin Interactions Reprogram Dendritic Cells to Promote Type 1 Anti-Tumor Immunity
Lensch V, Gabba A, Hincapie R, Bhagchandani S, Basak A, Alam M, Noble J, Irvine D, Shalek A, Johnson J, Finn M, Kiessling L. Carbohydrate-Lectin Interactions Reprogram Dendritic Cells to Promote Type 1 Anti-Tumor Immunity. ACS Nano 2024, 18: 26770-26783. PMID: 39283240, PMCID: PMC11646345, DOI: 10.1021/acsnano.4c07360.Peer-Reviewed Original ResearchCellular immunityDendritic cellsToll-like receptorsVirus-like particlesCD8<sup>+</sup> T cellsTumor-specific cellular immunityVaccine developmentCancer vaccine developmentInfiltrate solid tumorsMurine melanoma modelT cell functionInhibited tumor growthActivate TLR signalingTumor controlCancer immunotherapyCD4<sup>+</sup>Melanoma modelTLR7 agonistDC activationT cellsSolid tumorsTumor cellsTumor growthHumoral immunityVLP platformDevelopment of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC)
Kashima S, Gupta R, Moritz V, Sadak K, Adeniran A, Humphrey P, Dinulescu D, Palmer D, Hammond S, Bosenberg M, Hurwitz M, Kenney P, Braun D. Development of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC). The Oncologist 2024, 29: s5-s6. PMCID: PMC11301923, DOI: 10.1093/oncolo/oyae181.008.Peer-Reviewed Original ResearchRCC tumor microenvironmentPatient-derived tumor modelsRenal cell carcinomaImmune checkpoint inhibitorsT cell functionPeripheral blood mononuclear cellsEnzyme-linked immunosorbent assayTumor microenvironmentT cellsFlow cytometryTumor fragmentsIFN-gTumor modelTumor samplesCytokine productionHealthy donor peripheral blood mononuclear cellsImpact of immune checkpoint inhibitorsAnti-PD-1 monoclonal antibodyDonor peripheral blood mononuclear cellsCD4+CD25+ regulatory T cellsCD8+ T cell populationsResection of renal cell carcinomaSurgical resection of renal cell carcinomaAnti-PD-1 antibodyMetastatic renal cell carcinomaDeleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies
Wu M, Valenca-Pereira F, Cendali F, Giddings E, Pham-Danis C, Yarnell M, Novak A, Brunetti T, Thompson S, Henao-Mejia J, Flavell R, D’Alessandro A, Kohler M, Rincon M. Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies. Nature Communications 2024, 15: 4444. PMID: 38789421, PMCID: PMC11126743, DOI: 10.1038/s41467-024-48653-y.Peer-Reviewed Original ResearchConceptsMethylation-controlled J proteinCAR-T cellsEfficacy of adoptive T cell therapyCD8+ CAR T cellsAdoptive T cell therapyT-cell therapyCD8 cellsT cellsOvalbumin (OVA)-specific CD8T cell adoptive therapyCD8+ T cellsMelanoma tumors in vivoFunction of T cellsAdoptive cellular therapyMurine B-cell leukemiaPromote T cell functionB-cell leukemiaT cell functionTumors in vivoPre-clinical studiesAnti-tumor activityIn vivo efficacyAdoptive therapyPotential therapeutic strategyEndogenous negative regulatorThe FLRT3-UNC5B Pathway is a Novel Regulator of T Immunosurveillance
Flies D, Yan C, Yang Q, Arbitman S, Fitzgerald D, Sharee S, Shaik J, Bosiacki J, Myers K, Paucarmayta A, Johnson D, O'Neill T, Cusumano Z, Langermann S, Langenau D, Patel S. The FLRT3-UNC5B Pathway is a Novel Regulator of T Immunosurveillance. The Journal Of Immunology 2024, 212: 0298_5492-0298_5492. DOI: 10.4049/jimmunol.212.supp.0298.5492.Peer-Reviewed Original ResearchT cell activationT cellsCell-derived xenograftsTumor growthT cell anti-tumor immunityInhibitor of T cell activationCell-derived xenograft modelControl T cell responsesHuman T cell functionT cell checkpointsAnti-tumor immunityT cell responsesT cell functionActivated T cellsTumor-immune interactionsPromote tumor growthHuman T cellsCAR-TUNC-5 netrin receptor BZebrafish tumor modelTumor cellsTumor modelReceptor BGain-of-function screenMonoclonal antibodiesTumor expressed BCAM impedes anti-tumor T cell immunity and can be targeted therapeutically
Flies D, Tian L, O'Neill R, Fitzgerald D, Sharee S, Shaik J, Bosiacki J, Paucarmayta A, Prajapati K, Langermann S, Mrass P. Tumor expressed BCAM impedes anti-tumor T cell immunity and can be targeted therapeutically. The Journal Of Immunology 2024, 212: 0517_5466-0517_5466. DOI: 10.4049/jimmunol.212.supp.0517.5466.Peer-Reviewed Original ResearchAnti-tumor immunityT cell immunityCytotoxic T cellsTumor microenvironmentT cellsTumor growthAnti-tumor T cell immunityT cell anti-tumor immunityExclusion of T cellsIncreased T-cell infiltrationRegulating T cell immunityHuman T cell functionT cell infiltrationInhibitor of T cell proliferationT cell suppressionHuman tumors in vitroT cell functionReduced tumor growthT cell proliferationDecreased tumor growthTumors in vitroTumor growth in vivoCancer escapeCheckpoint inhibitorsGrowth in vivoMulti-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma.
Saad E, Labaki C, Miron B, Park J, Bakouny Z, Nassar A, Saliby R, Semaan K, Eid M, Meli K, Nabil Laimon Y, Geynisman D, Kokate R, Braun D, Signoretti S, McGregor B, Plimack E, Choueiri T, Van Allen E, Zibelman M. Multi-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma. Journal Of Clinical Oncology 2024, 42: 459-459. DOI: 10.1200/jco.2024.42.4_suppl.459.Peer-Reviewed Original ResearchMetastatic renal cell carcinomaImmune checkpoint inhibitorsTertiary lymphoid structuresWhole-exome sequencingDifferential gene expression analysisRenal cell carcinomaGene set enrichment analysisCheckpoint inhibitorsCell carcinomaB cellsAbsence of tertiary lymphoid structuresGene mutationsResistance to immune checkpoint inhibitorsPresence of tertiary lymphoid structuresImmune checkpoint inhibitor treatmentRNA-seqInitial response to therapyCD8+ T cell fractionCohort of ptsICI-based regimensDana-Farber Cancer InstituteT cell functionResponse to therapyNaive B cellsT-cell fraction
2023
Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation
Schnell A, Huang L, Regan B, Singh V, Vonficht D, Bollhagen A, Wang M, Hou Y, Bod L, Sobel R, Chihara N, Madi A, Anderson A, Regev A, Kuchroo V. Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation. Nature Immunology 2023, 24: 1908-1920. PMID: 37828379, PMCID: PMC10864036, DOI: 10.1038/s41590-023-01645-4.Peer-Reviewed Original ResearchConceptsPeptidoglycan recognition protein 1T cellsMyeloid cellsGenetic deletionPotent antitumor immune responsesCo-inhibitory moleculesExperimental autoimmune encephalomyelitisAntitumor immune responseImmune checkpoint blockadePromising targetSuccessful treatment optionT cell functionCentral nervous systemT cell activationMultiple human cancersAutoimmune neuroinflammationAntitumor immunityAutoimmune encephalomyelitisCheckpoint blockadeCheckpoint moleculesEffector phenotypeAutoimmune diseasesProinflammatory moleculesTissue inflammationTreatment optionsBSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS
Lu B, Lucca L, DiStasio M, Liu Y, Pham G, Buitrago-Pocasangre N, Arnal-Estape A, Moliterno J, Chiang V, Omuro A, Hafler D. BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS. Neuro-Oncology Advances 2023, 5: iii4-iii4. PMCID: PMC10402449, DOI: 10.1093/noajnl/vdad070.014.Peer-Reviewed Original ResearchT cell populationsT cell functionT cellsHigh-grade gliomasBrain metastasesHuman brain tumorsImmune cellsBrain tumorsNon-small cell lung cancer brain metastasesB cellsAnti-PD-1 therapy responseCell lung cancer brain metastasesLung cancer brain metastasesProductive antitumor immune responsesFollicular helper T cellsT-cell receptor sequencingTumor-infiltrating T cellsAntitumor T-cell functionCancer brain metastasesCo-inhibitory receptorsAntitumor immune responseCell receptor sequencingLonger overall survivalCell functionTertiary lymphoid structuresDifferential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.
Madden M, Ye X, Chi C, Fisher E, Wolf M, Needle G, Bader J, Patterson A, Reinfeld B, Landis M, Hathaway E, Muka J, O'Neil R, Karijolich J, Philip M, Rathmell J. Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells. The Journal Of Immunology 2023, 211: 563-575. PMID: 37341499, PMCID: PMC10526752, DOI: 10.4049/jimmunol.2200715.Peer-Reviewed Original ResearchConceptsCD8 T cellsT cellsActivated T cellsAntitumor CD8 T cellsCD8 T cell differentiationAdoptive transfer studiesMurine CD8 T cellsQ treatmentAdoptive cell therapyT cell functionT cell dependenceT cell differentiationT cell activationCB-839 treatmentAutoimmune diseasesFunctional outcomeTumor infiltrationTreatment strategiesGlucose metabolismCell activationTumor growthCB-839Cell therapyCell functionOxidative metabolismImmunogenetic 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 deficiencyIntrinsic B cell TLR-BCR linked coengagement induces class-switched, hypermutated, neutralizing antibody responses in absence of T cells
Rivera C, Zhou Y, Chupp D, Yan H, Fisher A, Simon R, Zan H, Xu Z, Casali P. Intrinsic B cell TLR-BCR linked coengagement induces class-switched, hypermutated, neutralizing antibody responses in absence of T cells. The Journal Of Immunology 2023, 210: 60.08-60.08. DOI: 10.4049/jimmunol.210.supp.60.08.Peer-Reviewed Original ResearchClass switch DNA recombinationGeneration of memory B cellsAbsence of T cellsMemory B cellsT cell helpNeutralizing antibody responsesPlasma cell differentiationAntibody responseT cellsB cellsCell differentiationAnti-microbial responsesSomatic hypermutationT cell compartmentT cell functionAntibodies to E. coliDeclining T cell functionAffinity maturation processS. typhimuriumDNA recombinationMature antibody responseAnamnestic antibody responseLate-stage responsesSalmonella flagellinPhysical linkageAP-1–independent NFAT signaling maintains follicular T cell function in infection and autoimmunity
Seth A, Yokokura Y, Choi J, Shyer J, Vidyarthi A, Craft J. AP-1–independent NFAT signaling maintains follicular T cell function in infection and autoimmunity. Journal Of Experimental Medicine 2023, 220: e20211110. PMID: 36820828, PMCID: PMC9998660, DOI: 10.1084/jem.20211110.Peer-Reviewed Original ResearchConceptsTfh cellsT cellsFollicular helper T cellsLupus-prone miceT cell subsetsTfh cell developmentHelper T cellsHumoral immune responseT cell functionGerminal center B cellsT cell statesRenal injuryAutoantibody productionCell subsetsPrimary T cellsImmune responseB cellsPharmacologic inhibitionTherapeutic insightsCell functionGenetic disruptionNFATCell developmentCellsGene expression
2022
Correlation between PD-L1 expression of the tumour cells and lymphocytes infiltration in the invasive front of urothelial carcinoma
Chen X, Chen H, Lin R, Li Y, Guo Y, Chen Q, Zhang Y, Cai G, Hu M, Chen G. Correlation between PD-L1 expression of the tumour cells and lymphocytes infiltration in the invasive front of urothelial carcinoma. Journal Of Clinical Pathology 2022, 77: 61-67. PMID: 36319076, PMCID: PMC10804014, DOI: 10.1136/jcp-2021-207795.Peer-Reviewed Original ResearchPD-L1 expressionUrothelial carcinomaOverall survivalPD-L1Tumor cellsCell infiltrationInvasive frontPD-1/PD-L1 signal pathwayNon-small cell lung cancerOS of patientsInvasive bladder urothelial carcinomaPD-L1 groupIndependent prognostic factorT cell infiltrationAdvanced bladder cancerCell lung cancerImmune cell infiltrationMore T cellsFirst new drugT cell functionBladder urothelial carcinomaMeans of immunohistochemistryLymphocyte infiltrationPD-1Prognostic factorsFirst-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Kim TW, Burris HA, de Miguel Luken MJ, Pishvaian MJ, Bang YJ, Gordon M, Awada A, Camidge DR, Hodi FS, McArthur GA, Miller WH, Cervantes A, Chow LQ, Lesokhin AM, Rutten A, Sznol M, Rishipathak D, Chen SC, Stefanich E, Pourmohamad T, Anderson M, Kim J, Huseni M, Rhee I, Siu LL. First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors. Clinical Cancer Research 2022, 28: of1-of12. PMID: 35699599, PMCID: PMC9662912, DOI: 10.1158/1078-0432.ccr-21-4020.Peer-Reviewed Original ResearchConceptsAdverse eventsImmune activationT cellsMost common treatment-related adverse eventsCommon treatment-related adverse eventsSolid tumorsTreatment-related adverse eventsRenal cell carcinoma patientsNon-small cell lung carcinomaRegulatory T cell functionTriple-negative breast cancerPD-1/PD-L1 antagonistsDose-escalation stageInfusion-related reactionsAdvanced solid tumorsRefractory solid tumorsCell carcinoma patientsDose-limiting toxicityEffector T cellsSubset of patientsFavorable safety profileHuman phase IPD-L1 antagonistsT cell functionCell lung carcinoma
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