Kavli Affiliate: Li Zhao
| Authors: Daniel Ranti, Haocheng Yu, Yuanshuo Wang, Christine Bieber, Trine Strandgaard, Berengere Salome, Sean Houghton, Junbum Kim, Hiranmayi Ravichandran, Iyinyeoluwa Okulate, Elliot Merritt, Sunjoo Bang, Alexandros Demetriou, Zhao Li, Sia Viborg Lindskrog, Dan Fu Ruan, Jorge Daza, Richa Rai, Everardo Hegewisch-Solloa, Emily Mace, Ruben Fernandez-Rodriguez, Sudeh Izadmehr, Glenn Doherty, Adam Farkas, Pamela Cruz-Encarnacion, Sanjana Shroff, Foramben Patel, Michelle Tran, Joy Park, Jingjing Qi, Manishkumar Patel, Daniel Geanon, Geoffrey Kelly, Ronaldo de Real, Brian Lee, Kai Nie, Sam Miake-Lye, Krista Angeliadis, Emir Radkevich, Tin Htwe Thin, Monica Garcia-Barros, Haley Brown, Bea Martin, Adonis Mateo, Alan Soto, Roni Sussman, Sheena Shiwlani, Sophia Francisco-Simon, Kristin Beaumont, Y Hu, Li Wang, Yin g-chih Wang, Robert Sebra, Steven Smith, Mihaela Skobe, Eleanor Clancy-Thompson, Douglas Palmer, Scott Hammond, Bejnamin Hopkins, Peter Wiklund, Jerry Zhu, Jose Javier Bravo-Cordero, Rachel Brody, Zhihong Chen, Seunghee Kim-Schulze, Lars Dyrskjot, Olivier Elemento, Anna Tocheva, Won Min Song, Nina Bhardwaj, Matthew Galsky, John P Sfakianos and Amir Horowitz bioRxiv. posted 3 September 2024
| Summary:
Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.