2023
Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.
Horowitch B, Lee D, Ding M, Martinez-Morilla S, Aung T, Ouerghi F, Wang X, Wei W, Damsky W, Sznol M, Kluger H, Rimm D, Ishizuka J. Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma. Clinical Cancer Research 2023, 29: 2908-2918. PMID: 37233452, PMCID: PMC10524955, DOI: 10.1158/1078-0432.ccr-23-0215.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsHuman melanoma cell linesMelanoma cell linesPD-L1Validation cohortYale-New Haven HospitalCombination of ipilimumabPD-L1 markersImmune checkpoint blockadePD-L1 biomarkerNew Haven HospitalSTAT1 levelsCell linesWestern blot analysisCheckpoint inhibitorsCheckpoint blockadeClinical responseOverall survivalImproved survivalResistance of cancersMetastatic melanomaMelanoma responsePredict responseTreatment responseDistinct patterns
2022
PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
Collins NB, Al Abosy R, Miller BC, Bi K, Zhao Q, Quigley M, Ishizuka JJ, Yates KB, Pope HW, Manguso RT, Shrestha Y, Wadsworth M, Hughes T, Shalek AK, Boehm JS, Hahn WC, Doench JG, Haining WN. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment. Journal For ImmunoTherapy Of Cancer 2022, 10: e003402. PMID: 35264433, PMCID: PMC8915320, DOI: 10.1136/jitc-2021-003402.Peer-Reviewed Original ResearchConceptsImmune evasionCheckpoint blockadePI3K activationMouse syngeneic tumor modelsPharmacological PI3K inhibitionEfficacy of immunotherapyNumber of CD8Tumor immune evasionTumor immune microenvironmentRational combination strategiesSyngeneic tumor modelsCell-extrinsic effectsK activationPI3K inhibitionMyeloid microenvironmentImmune microenvironmentPoor responseMyeloid infiltrationT cellsImmune responseImmunotherapyMyeloid cellsImmune systemPhospho-inositol-3 kinaseTumor microenvironment
2021
Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi AG, Ishizuka JJ, Kim SY, Klaeger S, Knudsen NH, Miller BC, Nguyen TH, Olander KE, Papanastasiou M, Rachimi S, Robitschek EJ, Schneider EM, Yeary MD, Zimmer MD, Jaffe JD, Carr SA, Doench JG, Haining WN, Yates KB, Manguso RT, Bernstein BE. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature 2021, 595: 309-314. PMID: 33953401, PMCID: PMC9166167, DOI: 10.1038/s41586-021-03520-4.Peer-Reviewed Original ResearchConceptsImmune checkpoint blockadeCheckpoint blockadeCytotoxic T cell responsesT cell responsesMouse tumor modelsImmune exclusionImmune clustersRetroviral antigensImmune sensitivityImmunostimulatory genesIntrinsic immunogenicityCell responsesTumor modelCentral mechanismsHuman tumorsCancer cellsBlockadeCandidate targetsImmunogenicity
2019
Author Correction: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, Manos M, Gjini E, Kuchroo JR, Ishizuka JJ, Collier JL, Griffin GK, Maleri S, Comstock DE, Weiss SA, Brown FD, Panda A, Zimmer MD, Manguso RT, Hodi FS, Rodig SJ, Sharpe AH, Haining WN. Author Correction: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nature Immunology 2019, 20: 1556-1556. PMID: 31582823, PMCID: PMC7461603, DOI: 10.1038/s41590-019-0528-5.Peer-Reviewed Original ResearchPhase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.
Konstantinopoulos PA, Luo W, Liu JF, Gulhan DC, Krasner C, Ishizuka JJ, Gockley AA, Buss M, Growdon WB, Crowe H, Campos S, Lindeman NI, Hill S, Stover E, Schumer S, Wright AA, Curtis J, Quinn R, Whalen C, Gray KP, Penson RT, Cannistra SA, Fleming GF, Matulonis UA. Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer. Journal Of Clinical Oncology 2019, 37: 2786-2794. PMID: 31461377, PMCID: PMC9798913, DOI: 10.1200/jco.19.01021.Peer-Reviewed Original ResearchConceptsPhase II studyEndometrial cancerObjective responseII studyMismatch repair-deficient (dMMR) solid tumorsMore mismatch repair proteinsEnd pointData cutoff dateMMRd endometrial cancersPersistent endometrial cancerTissue-agnostic approvalCoprimary end pointsPD-L1 statusPrimary end pointProgression-free survivalPD-L1 expressionPD-L1 inhibitorsCohort of patientsImmune checkpoint blockadeMismatch repair deficientUnacceptable toxicityCheckpoint blockadePatient selectionPolymerase chain reactionImmunohistochemical lossSubsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, Manos M, Gjini E, Kuchroo JR, Ishizuka JJ, Collier JL, Griffin GK, Maleri S, Comstock DE, Weiss SA, Brown FD, Panda A, Zimmer MD, Manguso RT, Hodi FS, Rodig SJ, Sharpe AH, Haining WN. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nature Immunology 2019, 20: 326-336. PMID: 30778252, PMCID: PMC6673650, DOI: 10.1038/s41590-019-0312-6.Peer-Reviewed Original ResearchConceptsTumor-infiltrating lymphocytesExhausted tumor-infiltrating lymphocytesT cell dysfunctionExhausted CD8T cellsCheckpoint blockadeCell dysfunctionAnti-PD-1 therapyInhibitory receptor PD-1Chronic viral infectionsExhausted T cellsReceptor PD-1Checkpoint blockade therapyDysfunctional CD8PD-1Antibody blockadeTumor controlSuch therapyCD8Viral infectionTumor growthExhausted cellsSpecific subpopulationsBlockadeTherapy
2018
Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, Iracheta-Vellve A, Miller BC, Du PP, Yates KB, Dubrot J, Buchumenski I, Comstock DE, Brown FD, Ayer A, Kohnle IC, Pope HW, Zimmer MD, Sen DR, Lane-Reticker SK, Robitschek EJ, Griffin GK, Collins NB, Long AH, Doench JG, Kozono D, Levanon EY, Haining WN. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 2018, 565: 43-48. PMID: 30559380, PMCID: PMC7241251, DOI: 10.1038/s41586-018-0768-9.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine DeaminaseAnimalsCell Cycle CheckpointsCell Line, TumorCRISPR-Cas SystemsDrug Resistance, NeoplasmFemaleHistocompatibility Antigens Class IImmunotherapyInflammationInterferon-Induced Helicase, IFIH1InterferonsMelanoma, ExperimentalMiceMice, Inbred C57BLPhenotypeProgrammed Cell Death 1 ReceptorReceptors, G-Protein-CoupledRNA EditingRNA, Double-StrandedRNA-Binding ProteinsConceptsImmune checkpoint blockadeCheckpoint blockadeAntigen presentationEffective anti-tumor immunityPD-1 checkpoint blockadeTumor cellsAnti-tumor immunityT cell recognitionSufficient inflammationImmunotherapy resistanceInhibitory checkpointsMost patientsInnate ligandsLoss of functionBlockadeTherapeutic requirementsLoss of ADAR1TumorsCancer cellsCell recognitionInflammationGrowth inhibitionADAR1PresentationCells