HLA-E and NKG2A Mediate Resistance toM. bovisBCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer
Author:
Ranti D., Yu H., Wang Y.A., Bieber C., Strandgaard T., Salomé B., Houghton Sean, 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.M.ORCID, Fernandez-Rodriguez R., Izadmehr S., Doherty G., Narasimhan A., Farkas A.M., Cruz-Encarnacion P., Shroff S., Patel F., Tran M., Park S.J., Qi J., Patel M., Geanon D., Kelly G., de Real R.M., Lee B., Nie K., Miake-Iye S., Angeliadis K., Radkevich E., Thin T.H., Garcia-Barros M., Brown H., Martin B., Mateo A., Soto A., Sussman R., Shiwlani S., Francisco-Simon S., Beaumont K.G., Hu Y., Wang Y-C., Wang L., Sebra R.P., Smith S., Skobe M., Clancy-Thompson E., Palmer D., Hammond S., Hopkins B. D., Wiklund P., Zhu J., Bravo-Cordero J.J., Brody R., Hopkins B., Chen Z.ORCID, Kim-Schulze S., Dyrskjøt L.ORCID, Elemento O., Tocheva A., Song W-M., Bhardwaj N., Galsky M.D., Sfakianos J.P., Horowitz A.
Abstract
AbstractMycobacterium bovisBacillus 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-EHIGHtumor 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.
Publisher
Cold Spring Harbor Laboratory
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