作者
Bérengère Salomé,John P. Sfakianos,Jorge Daza,Andrew Charap,Christian Hammer,Romain Banchereau,Adam M. Farkas,Daniel Geanon,Geoffrey Kelly,Ronaldo M. de Real,Brian Lee,Kristin G. Beaumont,Sanjana Shroff,Yuan Shuo A Wang,Ying-Chih Wang,Tin Htwe Thin,Mónica García-Barros,Everardo Hegewisch-Solloa,Emily M. Mace,Li Wang,Timothy J. O'Donnell,Diego Chowell,Rubén Fernández-Rodríguez,Mihaela Skobe,Nicole Taylor,Seunghee Kim-Schulze,Robert Sebra,Doug Palmer,Eleanor Clancy-Thompson,Scott A. Hammond,Alice O. Kamphorst,Karl-Johan Malmberg,Emanuela Marcenaro,Pedro Romero,Rachel Brody,Mathias Viard,Yuko Yuki,Maureen P. Martin,Mary Carrington,Reza Mehrazin,Peter Wiklund,Ira Mellman,Sanjeev Mariathasan,Jun Zhu,Matthew D. Galsky,Nina Bhardwaj,Amir Horowitz
摘要
Summary PD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Here, we show that KLRC1 (NKG2A) expression associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in CD8A high bladder 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.