HLA-E and NKG2A Mediate Resistance to <i>M. bovis</i> BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

ABSTRACT: 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-E^HIGH tumor

SUBMITTER: Ranti D 

PROVIDER: S-EPMC11398371 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature