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
Going viral: HBV-specific CD8+ tissue-resident memory T cells propagate anti-tumor immunity
Wei J, Ishizuka JJ. Going viral: HBV-specific CD8+ tissue-resident memory T cells propagate anti-tumor immunity. Immunity 2021, 54: 1630-1632. PMID: 34380061, DOI: 10.1016/j.immuni.2021.07.014.Commentaries, Editorials and LettersReprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence
Wu Z, Zhou J, Zhang X, Zhang Z, Xie Y, Liu JB, Ho ZV, Panda A, Qiu X, Cejas P, Cañadas I, Akarca FG, McFarland JM, Nagaraja AK, Goss LB, Kesten N, Si L, Lim K, Liu Y, Zhang Y, Baek JY, Liu Y, Patil DT, Katz JP, Hai J, Bao C, Stachler M, Qi J, Ishizuka JJ, Nakagawa H, Rustgi AK, Wong KK, Meyerson M, Barbie DA, Brown M, Long H, Bass AJ. Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature Genetics 2021, 53: 881-894. PMID: 33972779, PMCID: PMC9124436, DOI: 10.1038/s41588-021-00859-2.Peer-Reviewed Original ResearchMeSH Keywords3' Untranslated RegionsAdenosine DeaminaseAnimalsBase SequenceCarcinogenesisCell Line, TumorCell Transformation, NeoplasticCyclin-Dependent Kinase Inhibitor p16Endogenous RetrovirusesEnhancer Elements, GeneticEpigenomeEsophageal NeoplasmsEsophageal Squamous Cell CarcinomaGene Expression Regulation, NeoplasticGenome, HumanHumansInterferonsIntronsKruppel-Like Transcription FactorsMiceOrganoidsProtein BindingRNA, Double-StrandedRNA-Binding ProteinsSOXB1 Transcription FactorsTumor Suppressor Protein p53ConceptsRNA editing enzyme ADAR1Activity of oncogenesTranscription factor Sox2Chromatin remodelingSox2 bindingSOX2 activityTranscriptional landscapeEnzyme ADAR1Sox2 functionFactor Sox2Esophageal squamous cell carcinomaEsophageal organoidsTargetable vulnerabilitiesEndogenous retrovirusesSOX2Chromosome 3q amplificationSOX2 overexpressionPrecursor cellsP16 inactivationOncogeneEpigenomeCistromeNormal tissuesSquamous esophagusADAR1Epigenetic 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 targetsImmunogenicitySpatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma
Griffin GK, Weirather JL, Roemer MGM, Lipschitz M, Kelley A, Chen PH, Gusenleitner D, Jeter E, Pak C, Gjini E, Chapuy B, Rosenthal MH, Xu J, Chen BJ, Sohani AR, Lovitch SB, Abramson JS, Ishizuka J, Kim AI, Jacobson CA, LaCasce AS, Fletcher CD, Neuberg D, Freeman GJ, Hodi FS, Wright K, Ligon AH, Jacobsen ED, Armand P, Shipp MA, Rodig SJ. Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma. Blood 2021, 137: 1353-1364. PMID: 32871584, PMCID: PMC8555417, DOI: 10.1182/blood.2020006464.Peer-Reviewed Original ResearchConceptsT-cell/histiocyte-rich large B-cell lymphomaLarge B-cell lymphomaB-cell lymphomaMalignant B cellsDiffuse large B-cell lymphomaClassic Hodgkin lymphomaPD-1B cellsImmune signaturesImmune escapePD-1/PD-L1 pathwayPD-L1/PDImmune escape pathwayPD-1 blockadeImmune cell infiltratesPD-L1 expressionRefractory hematologic malignanciesPD-L1 pathwayMulti-institutional cohortClinical responsePartial responseCell infiltrateComplete responsePD-L1Aggressive variant
2020
Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor‐induced colitis
Grover S, Dougan M, Tyan K, Giobbie‐Hurder A, Blum SM, Ishizuka J, Qazi T, Elias R, Vora KB, Ruan AB, Martin‐Doyle W, Manos M, Eastman L, Davis M, Gargano M, Haq R, Buchbinder EI, Sullivan RJ, Ott PA, Hodi FS, Rahma OE. Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor‐induced colitis. Cancer 2020, 126: 3758-3767. PMID: 32567084, PMCID: PMC7381363, DOI: 10.1002/cncr.32966.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsVitamin D useVitamin D intakeICI colitisD intakeD useDiscovery cohortDevelopment of ICIsImmune checkpoint inhibitor-induced colitisCheckpoint inhibitor-induced colitisCombination immune checkpoint inhibitorsMultivariable logistic regression analysisDana-Farber Cancer InstituteRisk of colitisMultivariable regression analysisLogistic regression analysisMassachusetts General HospitalRegression analysisCheckpoint inhibitorsLaboratory characteristicsPD-1Ulcerative colitisLymphocyte ratioMelanoma patientsVitamin D
2019
Phase 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