NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer
Author:
Salomé Bérengère, Sfakianos John P., Daza Jorge, Charap Andrew, Hammer Christian, Banchereau Romain, Farkas Adam M., Geanon Daniel, Kelly Geoffrey, de Real Ronaldo M., Lee Brian, Beaumont Kristin G., Shroff Sanjana, Wang Yuan Shuo A., Wang Ying-chih, Thin Tin Htwe, Garcia-Barros Monica, Hegewisch-Solloa Everardo, Mace Emily M.ORCID, 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 Maureen, Carrington Mary, Mehrazin Reza, Wiklund Peter, Mellman Ira, Mariathasan Sanjeev, Zhu Jun, Galsky Matthew D., Bhardwaj Nina, Horowitz Amir
Abstract
SummaryPD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Here, we show thatKLRC1(NKG2A) expression associates with improved survival and responsiveness to PD-L1 blockade immunotherapy inCD8Ahighbladder tumors. The loss of antigen presentation is a common mechanism for tumor escape in bladder cancer. NKG2A+CD8 T cells are able to circumvent HLA-ABC loss through TCR-independent cytotoxicity, which is partly mediated by DNAM-1. In bladder tumors, NKG2A is acquired on a subset of PD-1+CD8 T cells, alongside stronger tissue-residency memory features, TCR-independent cytotoxicity and evidence of recent proliferation. HLA-E is low but variably expressed on bladder tumors. When expressed, NKG2A+CD8 T cell anti-tumor responses to HLA-ABC-deficient tumors are inhibited and partly restored upon NKG2A blockade. Overall, our study identifies an alternative path for CD8 T cell exhaustion, that is mediated by NKG2A upregulation and TCR-independent cytotoxicity.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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