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

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

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish
Pages (from-to)1027-1043.e9
JournalCancer Cell
Issue number9
StatePublished - 12 Sep 2022


  • CD8 T cells
  • HLA class I
  • NK cells
  • NKG2A
  • bladder cancer
  • checkpoint blockade immunotherapy
  • immune exhaustion
  • solid tumors
  • tumor microenvironment


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