2024
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight J, López-Giráldez F, Choi H, Socci N, Merghoub T, Awad M, Getz G, Gainor J, Hellmann M, Caron É, Kaech S, Politi K. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. Journal Of Experimental Medicine 2024, 222: e20231106. PMID: 39585348, DOI: 10.1084/jem.20231106.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsNon-small cell lung cancerAcquired resistanceCheckpoint inhibitorsResistant tumorsPatients treated with anti-PD-1/PD-L1 therapyAnti-PD-1/PD-L1 therapyLung cancerResistance to immune checkpoint inhibitorsAssociated with decreased progression-free survivalHypoxia activated pro-drugsTargeting hypoxic tumor regionsTreat non-small cell lung cancerAnti-CTLA-4Anti-PD-1Immune checkpoint inhibitionTumor metabolic featuresProgression-free survivalCell lung cancerResistant cancer cellsHypoxic tumor regionsMHC-II levelsRegions of hypoxiaKnock-outCheckpoint inhibitionG9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1
Exposito F, Redrado M, Serrano D, Calabuig-Fariñas S, Bao-Caamano A, Gallach S, Jantus-Lewintre E, Diaz-Lagares A, Rodriguez-Casanova A, Sandoval J, San Jose-Eneriz E, Garcia J, Redin E, Senent Y, Leon S, Pio R, Lopez R, Oyarzabal J, Pineda-Lucena A, Agirre X, Montuenga L, Prosper F, Calvo A. G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1. Cell Death & Disease 2024, 15: 787. PMID: 39488528, PMCID: PMC11531574, DOI: 10.1038/s41419-024-07156-w.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerNon-small cell lung cancer patientsCM-272Treatment of non-small cell lung cancerReprogram tumor cellsAssociated with poor prognosisResponse to chemotherapyCell lung cancerCancer drugsMonitor tumor progressionOverexpression of G9aNSCLC cell linesLung cancer growthCancer drug sensitivityNon-small cell lung cancer growthNon-invasive biomarkersTumor volumeAntitumor efficacyTargeted therapyPoor prognosisCancer modelsTumor cellsInduce cell deathTumor progressionLung cancer
2023
PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.
Exposito F, Redrado M, Houry M, Hastings K, Molero-Abraham M, Lozano T, Solorzano J, Sanz-Ortega J, Adradas V, Amat R, Redin E, Leon S, Legarra N, Garcia J, Serrano D, Valencia K, Robles-Oteiza C, Foggetti G, Otegui N, Felip E, Lasarte J, Paz-Ares L, Zugazagoitia J, Politi K, Montuenga L, Calvo A. PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells. Cancer Research 2023, 83: 2513-2526. PMID: 37311042, DOI: 10.1158/0008-5472.can-22-3023.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerLung squamous carcinomaAnti-PD-1 therapyRegulatory T cellsCell lung cancerImmunosuppressive microenvironmentLung cancerImmunotherapy resistanceT cellsWorse progression-free survivalCell death protein 1PTEN lossAnti-TGFβ antibodyConversion of CD4PI3K/AKT/mTOR pathwayProgression-free survivalDeath protein 1Treatment of miceImmunosuppressive tumor microenvironmentPTEN/PI3K/AKT/mTOR pathwayAKT/mTOR pathwayPD-L1TLR agonistsTumor rejectionSquamous carcinoma
2021
SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation
Redin E, Garmendia I, Lozano T, Serrano D, Senent Y, Redrado M, Villalba M, De Andrea CE, Exposito F, Ajona D, Ortiz-Espinosa S, Remirez A, Bertolo C, Sainz C, Garcia-Pedrero J, Pio R, Lasarte J, Agorreta J, Montuenga LM, Calvo A. SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation. Journal For ImmunoTherapy Of Cancer 2021, 9: e001496. PMID: 33658304, PMCID: PMC7931761, DOI: 10.1136/jitc-2020-001496.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationDasatinibDrug Resistance, NeoplasmFemaleHumansImmune Checkpoint InhibitorsLung NeoplasmsLymphocytes, Tumor-InfiltratingMiceMice, 129 StrainPhenotypeProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsProto-Oncogene Proteins c-yesSignal TransductionT-Lymphocytes, RegulatoryTumor MicroenvironmentConceptsNon-small cell lung cancerNumber of TregsMultiplex immunofluorescenceAntiprogrammed cell death 1 (PD-1) antibodySrc family kinase (SFK) inhibitor dasatinibTumor growthInhibitor dasatinibCell death 1 antibodyYES1 expressionDeath-1 antibodyImmune cytotoxic activityPD-1 treatmentPD-1/Treg cell conversionUse of dasatinibVivo depletion experimentsAntitumor activityImmune checkpoint inhibitorsOutcomes of patientsProtein expressionCohort of patientsManagement of patientsCell lung cancerRelevant mouse modelVivo drug testing
2020
Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade
Ajona D, Ortiz-Espinosa S, Lozano T, Exposito F, Calvo A, Valencia K, Redrado M, Remírez A, Lecanda F, Alignani D, Lasarte J, Macaya I, Senent Y, Bértolo C, Sainz C, Gil-Bazo I, Eguren-Santamaría I, Lopez-Picazo J, Gonzalez A, Perez-Gracia J, de Andrea C, Vicent S, Sanmamed M, Montuenga L, Pio R. Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nature Cancer 2020, 1: 75-85. PMID: 35121837, DOI: 10.1038/s43018-019-0007-9.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarcinoma, Non-Small-Cell LungHumansImmune Checkpoint InhibitorsInsulin-Like Growth Factor ILung NeoplasmsMiceProgrammed Cell Death 1 ReceptorConceptsPD-1 blockadeCell death protein 1 (PD-1) pathwayPD-1 immune checkpoint blockadeCD8/Treg ratioHigh IGF-1R expressionInsulin-like growth factor-1Cell lung cancer treatmentIGF-1 levelsPD-1 inhibitionImmune checkpoint blockadeTumor-specific immunityCell lung cancerIGF-1R expressionHigher plasma levelsLung cancer progressionLung cancer treatmentIGF-1 receptorGrowth factor-1Protein 1 pathwayTreg ratioCD8 cellsCheckpoint blockadePD-1Syngeneic modelLung cancer