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

Single-cell RNA sequencing data used in the following article:

NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00369-5

Authors:
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, Yuan Shuo A. Wang, Ying-chih Wang, Tin Htwe Thin, Monica 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*

Summary
PD-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 HLA class I-deficient tumors using 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.

单细胞RNA测序数据，用于以下文章：

NKG2A和HLA-E定义了膀胱癌中的一种替代性免疫检查点轴
https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00369-5

作者：
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, Yuan Shuo A. Wang, Ying-chih Wang, Tin Htwe Thin, Monica 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*

摘要：PD-1/PD-L1阻断免疫疗法在膀胱癌治疗中疗效有限。本研究揭示了NKG2A与膀胱肿瘤中CD8+ T细胞高丰度相关，可改善患者的生存率和对PD-L1阻断免疫疗法的反应性。在膀胱肿瘤中，NKG2A在CD8+ T细胞上的获得晚于PD-1以及其他已建立的免疫检查点。NKG2A+ PD-1+ CD8+ T细胞通过其依赖TCR的非典型性先天机制对HLA I类缺陷性肿瘤的反应能力，与传统定义的耗竭性T细胞相区别。随着疾病进展，膀胱肿瘤的HLA-ABC表达逐渐减弱，突显了靶向非TCR依赖性抗肿瘤功能的重要性。值得注意的是，当肿瘤表达HLA-E时，NKG2A+ CD8+ T细胞受到抑制，在NKG2A阻断后，其抑制状态部分恢复，这种恢复依赖于HLA-E。总的来说，本研究为后续临床试验提供了框架，该试验将NKG2A阻断与其他针对T细胞的免疫疗法相结合，适用于肿瘤中HLA-E表达水平较高的病例。