BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• High-risk nonmuscle-invasive bladder cancer (NMIBC) often recurs after bacillus Calmette-Guérin (BCG) immunotherapy.
• Mechanisms of BCG resistance and treatment failure in bladder cancer are not well understood.

Purpose of the Study:

• To investigate the distinct patterns of immune subversion following BCG therapy in bladder cancer.
• To identify biomarkers predicting patient outcomes after BCG treatment for NMIBC.

Main Methods:

• Analysis of cancer cell lines, human bladder tumors, and patient samples before and after BCG therapy.
• Assessment of HLA-I membrane expression, autophagy flux, tumor microenvironment (TME), epithelial-mesenchymal transition (EMT), and immune cell infiltrates.
• Immunohistochemistry (IHC) for HLA-I scoring.

Main Results:

• Two patterns of immune subversion identified: 1) Intracellular BCG infection downregulating HLA-I via autophagy inhibition, leading to a myeloid-suppressive TME, EMT, and dismal outcomes. 2) HLA-I proficient cancer cells associated with CD8+ T cell infiltration, inflammatory cytokines, and favorable outcomes.
• HLA-I expression loss at relapse is attributed to BCG-induced immune subversion, not immunoediting.
• HLA-I scoring via IHC can stratify patient prognosis.

Conclusions:

• BCG relapse in NMIBC is characterized by distinct immune evasion strategies involving HLA-I expression.
• HLA-I deficiency predicts a poor prognosis and a myeloid-suppressive TME.
• HLA-I expression status is a valuable prognostic biomarker for stratifying treatment strategies in urothelial cancer.