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NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer

  1. Author:
    Salomé, Bérengère
    Sfakianos, John P
    Ranti, Daniel
    Daza, Jorge
    Bieber, Christine
    Charap, Andrew
    Hammer, Christian
    Banchereau, Romain
    Farkas, Adam M
    Ruan, Dan Fu
    Izadmehr, Sudeh
    Geanon, Daniel
    Kelly, Geoffrey
    de Real, Ronaldo M
    Lee, Brian
    Beaumont, Kristin G
    Shroff, Sanjana
    Wang, Yuanshuo A
    Wang, Ying-Chih
    Thin, Tin Htwe
    Garcia-Barros, Monica
    Hegewisch-Solloa, Everardo
    Mace, Emily M
    Wang, Li
    O'Donnell, Timothy
    Chowell, Diego
    Fernandez-Rodriguez, Ruben
    Skobe, Mihaela
    Taylor, Nicole
    Kim-Schulze, Seunghee
    Sebra, Robert P
    Palmer, Doug
    Clancy-Thompson, Eleanor
    Hammond, Scott
    Kamphorst, Alice O
    Malmberg, Karl-Johan
    Marcenaro, Emanuela
    Romero, Pedro
    Brody, Rachel
    Viard,Mathias
    Yuki,Yuko
    Martin,Pat
    Carrington,Mary
    Mehrazin, Reza
    Wiklund, Peter
    Mellman, Ira
    Mariathasan, Sanjeev
    Zhu, Jun
    Galsky, Matthew D
    Bhardwaj, Nina
    Horowitz, Amir

  2. Author Address

    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., 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., Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA; Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA., Department of Oncology Biomarker Development, Genentech, South San Francisco, CA 94080, USA., 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., Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., 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., Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA., 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., 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., 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., AstraZeneca, Oncology R & D Unit, Gaithersburg, MD 20878, USA., 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., Department of Experimental Medicine, University of Genoa, Genoa, Italy., Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA., Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA., 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., 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.,
    1. Year: 2022
    2. Date: Sep 12
  2. Journal: Cancer Cell
    1. 40
    2. 9
    3. Pages: 1027-1043.e9
  4. Type of Article: Article
  1. Abstract:

    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. Copyright © 2022 Elsevier Inc. All rights reserved.

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  2. DOI: 10.1016/j.ccell.2022.08.005
  3. PMID: 36099881
  4. PMCID: PMC9479122
  5. PII : S1535-6108(22)00369-5

Library Notes

  1. Fiscal Year: FY2022-2023
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