PMID- 36099881
OWN - NLM
STAT- MEDLINE
DCOM- 20220915
LR  - 20240216
IS  - 1878-3686 (Electronic)
IS  - 1535-6108 (Print)
IS  - 1535-6108 (Linking)
VI  - 40
IP  - 9
DP  - 2022 Sep 12
TI  - NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.
PG  - 1027-1043.e9
LID - S1535-6108(22)00369-5 [pii]
LID - 10.1016/j.ccell.2022.08.005 [doi]
AB  - Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade 
      immunotherapies have limited efficacy in the treatment of bladder cancer. Here, 
      we show that NKG2A associates with improved survival and responsiveness to PD-L1 
      blockade immunotherapy in bladder tumors that have high abundance of CD8(+) 
      T cells. In bladder tumors, NKG2A is acquired on CD8(+) T cells later than PD-1 
      as well as other well-established immune checkpoints. NKG2A(+) PD-1(+) CD8(+) 
      T cells diverge from classically defined exhausted T cells through their ability 
      to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell 
      receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder 
      tumors is progressively diminished as disease progresses, framing the importance 
      of targeting TCR-independent anti-tumor functions. Notably, NKG2A(+) CD8(+) 
      T cells are inhibited when HLA-E is expressed by tumors and partly restored upon 
      NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a 
      framework for subsequent clinical trials combining NKG2A blockade with other 
      T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Salome, Berengere
AU  - Salome B
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Sfakianos, John P
AU  - Sfakianos JP
AD  - Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 
      10029, USA.
FAU - Ranti, Daniel
AU  - Ranti D
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Daza, Jorge
AU  - Daza J
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Bieber, Christine
AU  - Bieber C
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Charap, Andrew
AU  - Charap A
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA; Department of Urology, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Hammer, Christian
AU  - Hammer C
AD  - Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA; 
      Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA.
FAU - Banchereau, Romain
AU  - Banchereau R
AD  - Department of Oncology Biomarker Development, Genentech, South San Francisco, CA 
      94080, USA.
FAU - Farkas, Adam M
AU  - Farkas AM
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Division of Hematology and 
      Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Ruan, Dan Fu
AU  - Ruan DF
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Izadmehr, Sudeh
AU  - Izadmehr S
AD  - Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School 
      of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Geanon, Daniel
AU  - Geanon D
AD  - Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Kelly, Geoffrey
AU  - Kelly G
AD  - Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - de Real, Ronaldo M
AU  - de Real RM
AD  - Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Lee, Brian
AU  - Lee B
AD  - Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Beaumont, Kristin G
AU  - Beaumont KG
AD  - Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, 
      New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn 
      School of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Shroff, Sanjana
AU  - Shroff S
AD  - Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, 
      New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn 
      School of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Wang, Yuanshuo A
AU  - Wang YA
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Wang, Ying-Chih
AU  - Wang YC
AD  - Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, 
      New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn 
      School of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Thin, Tin Htwe
AU  - Thin TH
AD  - Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Garcia-Barros, Monica
AU  - Garcia-Barros M
AD  - Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Hegewisch-Solloa, Everardo
AU  - Hegewisch-Solloa E
AD  - Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia 
      University, New York, NY 10032, USA.
FAU - Mace, Emily M
AU  - Mace EM
AD  - Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia 
      University, New York, NY 10032, USA.
FAU - Wang, Li
AU  - Wang L
AD  - Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, 
      New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn 
      School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, a Mount Sinai 
      Venture, Stamford, CT 06902, USA.
FAU - O'Donnell, Timothy
AU  - O'Donnell T
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Division of Hematology and 
      Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Chowell, Diego
AU  - Chowell D
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Fernandez-Rodriguez, Ruben
AU  - Fernandez-Rodriguez R
AD  - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Skobe, Mihaela
AU  - Skobe M
AD  - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Taylor, Nicole
AU  - Taylor N
AD  - Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School 
      of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Kim-Schulze, Seunghee
AU  - Kim-Schulze S
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Human Immune Monitoring Center, 
      Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Sebra, Robert P
AU  - Sebra RP
AD  - Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, 
      New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn 
      School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, a Mount Sinai 
      Venture, Stamford, CT 06902, USA; Black Family Stem Cell Institute, Icahn School 
      of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Palmer, Doug
AU  - Palmer D
AD  - AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA.
FAU - Clancy-Thompson, Eleanor
AU  - Clancy-Thompson E
AD  - AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA.
FAU - Hammond, Scott
AU  - Hammond S
AD  - AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA.
FAU - Kamphorst, Alice O
AU  - Kamphorst AO
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA.
FAU - Malmberg, Karl-Johan
AU  - Malmberg KJ
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 
      Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Marcenaro, Emanuela
AU  - Marcenaro E
AD  - Department of Experimental Medicine, University of Genoa, Genoa, Italy.
FAU - Romero, Pedro
AU  - Romero P
AD  - Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland.
FAU - Brody, Rachel
AU  - Brody R
AD  - Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Viard, Mathias
AU  - Viard M
AD  - Basic Science Program, Frederick National Laboratory for Cancer Research, 
      Frederick, MD 21701, USA.
FAU - Yuki, Yuko
AU  - Yuki Y
AD  - Basic Science Program, Frederick National Laboratory for Cancer Research, 
      Frederick, MD 21701, USA.
FAU - Martin, Maureen
AU  - Martin M
AD  - Basic Science Program, Frederick National Laboratory for Cancer Research, 
      Frederick, MD 21701, USA.
FAU - Carrington, Mary
AU  - Carrington M
AD  - Basic Science Program, Frederick National Laboratory for Cancer Research, 
      Frederick, MD 21701, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, 
      MA, USA.
FAU - Mehrazin, Reza
AU  - Mehrazin R
AD  - Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 
      10029, USA.
FAU - Wiklund, Peter
AU  - Wiklund P
AD  - Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 
      10029, USA.
FAU - Mellman, Ira
AU  - Mellman I
AD  - Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
FAU - Mariathasan, Sanjeev
AU  - Mariathasan S
AD  - Department of Oncology Biomarker Development, Genentech, South San Francisco, CA 
      94080, USA.
FAU - Zhu, Jun
AU  - Zhu J
AD  - Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, 
      New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn 
      School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, a Mount Sinai 
      Venture, Stamford, CT 06902, USA.
FAU - Galsky, Matthew D
AU  - Galsky MD
AD  - Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School 
      of Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Bhardwaj, Nina
AU  - Bhardwaj N
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Division of Hematology and 
      Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA. Electronic address: nina.bhardwaj@mssm.edu.
FAU - Horowitz, Amir
AU  - Horowitz A
AD  - The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological 
      Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New 
      York, NY 10029, USA. Electronic address: amir.horowitz@mssm.edu.
LA  - eng
GR  - R21 AI130760/AI/NIAID NIH HHS/United States
GR  - F31 AI164869/AI/NIAID NIH HHS/United States
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - P30 CA196521/CA/NCI NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - T32 CA078207/CA/NCI NIH HHS/United States
GR  - R01 CA201189/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Cancer Cell
JT  - Cancer cell
JID - 101130617
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (KLRC1 protein, human)
RN  - 0 (NK Cell Lectin-Like Receptor Subfamily C)
RN  - 0 (Programmed Cell Death 1 Receptor)
SB  - IM
MH  - B7-H1 Antigen/metabolism
MH  - CD8-Positive T-Lymphocytes
MH  - Histocompatibility Antigens Class I
MH  - Humans
MH  - NK Cell Lectin-Like Receptor Subfamily C/*metabolism
MH  - Programmed Cell Death 1 Receptor
MH  - *Urinary Bladder Neoplasms/therapy
MH  - HLA-E Antigens
PMC - PMC9479122
MID - NIHMS1830631
OTO - NOTNLM
OT  - CD8 T cells
OT  - HLA class I
OT  - NK cells
OT  - NKG2A
OT  - bladder cancer
OT  - checkpoint blockade immunotherapy
OT  - immune exhaustion
OT  - solid tumors
OT  - tumor microenvironment
COIS- Declaration of interests L.W., R.P.S., and J.Z. are employees of Sema4. A.H. 
      receives research funds from Zumutor Biologics and is on the advisory boards of 
      HTG Molecular Diagnostics, Immunorizon, UroGen, and Takeda. N.B. is an extramural 
      member of the Parker Institute for Cancer Immunotherapy; receives research funds 
      from Regeneron, Harbor Biomedical, DC Prime, and Dragonfly Therapeutics; and is 
      on the advisory boards of Neon Therapeutics, Novartis, Avidea, Boehringer 
      Ingelheim, Rome Therapeutics, Rubius Therapeutics, Roswell Park Comprehensive 
      Cancer Center, BreakBio, Carisma Therapeutics, CureVac, Genotwin, BioNTech, 
      Gilead Therapeutics, Tempest Therapeutics, and the Cancer Research Institute. A 
      patent related to this work was filed to the United States Patent and Trademark 
      Office (63/313,823).
EDAT- 2022/09/14 06:00
MHDA- 2022/09/16 06:00
PMCR- 2023/09/12
CRDT- 2022/09/13 18:28
PHST- 2021/12/16 00:00 [received]
PHST- 2022/06/24 00:00 [revised]
PHST- 2022/08/05 00:00 [accepted]
PHST- 2022/09/13 18:28 [entrez]
PHST- 2022/09/14 06:00 [pubmed]
PHST- 2022/09/16 06:00 [medline]
PHST- 2023/09/12 00:00 [pmc-release]
AID - S1535-6108(22)00369-5 [pii]
AID - 10.1016/j.ccell.2022.08.005 [doi]
PST - ppublish
SO  - Cancer Cell. 2022 Sep 12;40(9):1027-1043.e9. doi: 10.1016/j.ccell.2022.08.005.