ArticlebioRxiv : the preprint server for biology2025
HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.
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81 authors.
D RantiDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
H YuDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
B SaloméDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
S BangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
I DuquesneDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Y A WangDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
C BieberDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
T StrandgaardDepartment of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
E MerrittThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
G DohertyDivision of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
A NarasimhanDivision of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
I OkulateDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sean HoughtonCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
B HugDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J KimCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
H RavichandranCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
A DemetriouDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Z LiDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
S V LindskrogDepartment of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
A N M Rangel da SilvaDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
D F RuanDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J DazaDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J Cris InglesDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
R RaiTisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
E Hegewisch-SolloaDepartment of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York NY, USA.
E M MaceDepartment of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York NY, USA.ORCID 0000-0003-0226-7393
R Fernandez-RodriguezDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
S IzadmehrTisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
A M FarkasThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
P Cruz-EncarnacionDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
S ShroffDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
F PatelThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
M TranThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
D YoussefThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
A AnanthanarayananThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J ParkDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
D GeanonHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
G KellyHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
B LeeHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
K NieHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
S Miake-LyeHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
H XieHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
R ChenHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
C BiHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
T RizakosHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
B VillagomezHuman Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
T H ThinDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
M Garcia-BarrosDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
H BrownDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
B MartinDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
A MateoDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
A SotoDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
R SussmanDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
S ShiwlaniDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
S Francisco-SimonDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
K G BeaumontDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Y-C WangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
L WangDivision of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
R P SebraDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
S SmithCentre for Inflammation Research and Translational Medicine, Department of Biosciences, Brunel University of London, London, UK.
M SkobeDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
E Clancy-ThompsonAstraZeneca, Oncology R & D Unit, Gaithersburg, Maryland, USA.
D PalmerAstraZeneca, Oncology R & D Unit, Gaithersburg, Maryland, USA.
S HammondAstraZeneca, Oncology R & D Unit, Gaithersburg, Maryland, USA.
P YolmoDepartment of Biomedical and Molecular Sciences, Cancer Research Institute, Queen's University, Kingston, ON, CANADA.
M KotiDepartment of Biomedical and Molecular Sciences, Cancer Research Institute, Queen's University, Kingston, ON, CANADA.
B D HopkinsCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
P WiklundDepartment of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J ZhuDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J J Bravo-CorderoDivision of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
R BrodyDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Z ChenDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0001-7403-7015
S Kim-SchulzeDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
L DyrskjøtDepartment of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.ORCID 0000-0001-7061-9851
O ElementoCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
A TochevaThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
W-M SongDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
N BhardwajThe Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
M D GalskyTisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
J P SfakianosDepartment of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
A HorowitzDepartment of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Funding
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANTP30CA196521 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Deanna L Benson · 2015 to 2026
$35.4MBridge2AI: Voice as a Biomarker of Health - Building an ethically sourced, bioaccoustic database to understand disease like never beforeOT2OD032720 · OD · UNIVERSITY OF SOUTH FLORIDA · PI BENSOUSSAN, YAEL EMILIE, BÉLISLE-PIPON, JEAN-CHRISTOPHE · 2022 to 2025
$18.0MProject 2U19AI168632 · NIAID · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI Octavio Ramilo · 2022 to 2026
$10.2MElucidating single cell changes in neurogenic brain regions during HIV and cannabinoid exposureU01DA058527 · NIDA · WEILL MEDICAL COLL OF CORNELL UNIV · PI Michael Jay Corley, Lishomwa C Ndhlovu · 2023 to 2026
$9.4MTargeting the BCL2 immune checkpoint to enhance the immunostimulatory effects of radiation in breast cancerR01CA271915 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI Lorenzo Galluzzi · 2023 to 2026
$2.9MImmunoregulatory role of lung-resident club cell factors in lung cancerR01CA271545 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI NASSER Khaled ALTORKI, Vivek Mittal · 2023 to 2026
$2.7MHLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancerR01CA269954 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Amir Horowitz, John Sfakianos · 2023 to 2026
$2.7MER stress-driven IRE1a-XBP1 signaling in lung cancerR01CA271619 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI Juan R Cubillos-Ruiz, Vivek Mittal · 2023 to 2026
$2.6MA Mass Spectrometry Approach to the Genetic and Epigenetic Mechanisms Controlling Neuronal IdentityR01NS111997 · NINDS · WEILL MEDICAL COLL OF CORNELL UNIV · PI DAHMANE, NADIA, GARCIA, BENJAMIN A · 2020 to 2024
$2.6MIntegrative network modeling of bulk and single-cell sequencing data to characterize multi-scale cell architectureR35GM142918 · NIGMS · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI SONG, WON-MIN · 2021 to 2025
$2.1MThe joint WCM-NYGC Center for Functional and Clinical Interpretation of Tumor ProfilesU24CA264032 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI ELEMENTO, OLIVIER, ROBINE, NICOLAS · 2021 to 2025
$2.0MDefining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancyR01CA244780 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI BRAVO-CORDERO, JOSE JAVIER · 2020 to 2024
$1.9MNCI NIH HHS OT2 CA297580NCI NIH HHS P30 CA196521NCI NIH HHS R01 CA244780NCI NIH HHS R01 CA269954NCI NIH HHS R01 CA271545NCI NIH HHS R01 CA271619NCI NIH HHS R01 CA271915NCI NIH HHS R01 CA301050NCI NIH HHS R21 CA274148NCI NIH HHS R61 CA278402NCI NIH HHS U24 CA264032NIAID NIH HHS R01 AI187598NIAID NIH HHS R21 AI130760NIAID NIH HHS U19 AI168632NIDA NIH HHS U01 DA058527NIGMS NIH HHS R35 GM142918NIH HHS OT2 OD032720NINDS NIH HHS R01 NS111997NINDS NIH HHS R01 NS127984
Abstract
Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-E
Indexed as
BCG-unresponsiveImmunotherapyNK cellsNon-muscle-invasive bladder cancer
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