HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer
Ranti, D.; Yu, H.; Wang, Y.; Bieber, C.; Strandgaard, T.; Salome, B.; Houghton, S.; Kim, J.; Ravichandran, H.; Okulate, I.; Merritt, E.; Bang, S.; Demetriou, A.; Li, Z.; Lindskrog, S. V.; Ruan, D. F.; Daza, J.; Rai, R.; Hegewisch-Solloa, E.; Mace, E.; Fernandez-Rodriguez, R.; Izadmehr, S.; Doherty, G.; Farkas, A.; Cruz-Encarnacion, P.; Shroff, S.; Patel, F.; Tran, M.; Park, J.; Qi, J.; Patel, M.; Geanon, D.; Kelly, G.; de Real, R.; Lee, B.; Nie, K.; Miake-Lye, S.; Angeliadis, K.; Radkevich, E.; Thin, T. H.; Garcia-Barros, M.; Brown, H.; Martin, B.; Mateo, A.; Soto, A.; Sussman, R.; Shiwlani, S
Show abstract
Bacillus Calmette-Guerin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-{gamma}exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.
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