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Immune checkpoint B7x promotes immune evasion and resistance to PD-1/PD-L1 blockade in bladder cancer
Marc C Pulanco1,2, Xiang Yu Zheng2,3, Alexander Sankin2,4
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York 10461, USA.
Abstract:
Cancer cells adopt multiple strategies to avoid detection and destruction by the immune system, including exploiting immune checkpoint pathways. B7x (B7-H4, B7S1, or VTCN1), a member of the B7/CD28 family, is frequently expressed in advanced bladder cancer, yet its role in bladder cancer progression and resistance to therapy remains poorly understood. Resistance to PD-1/PD-L1 immune checkpoint blockade immunotherapy significantly limits durable responses, with only 20%-25% of patients with muscle-invasive bladder cancer (MIBC) achieving long-term benefits. Here, we demonstrated that B7x mRNA and protein expression were associated with poor survival outcomes in MIBC patients and mouse models of bladder cancer, respectively. Stable expression of B7x in immune-competent bladder cancer mouse models resulted in enhanced tumor growth and splenomegaly, driven by the exclusion and suppression of tumor-infiltrating antitumor immune cells and the enrichment of pro-tumor and immunosuppressive cells. Consistently, in the IMvigor210 clinical trial, high B7x mRNA expression was correlated with poorer survival in MIBC patients treated with PD-L1 blockade. Notably, combination therapy targeting B7x alongside PD-1/PD-L1 or CTLA-4 blockade reduced tumor burden and overcame resistance to monotherapy. These findings establish B7x as a substantial driver of immune evasion in bladder cancer and highlight its potential as a therapeutic target to improve immune checkpoint blockade efficacy in MIBC.
Insights
B7x expression drives immune evasion in bladder cancer, hindering immunotherapy. Targeting B7x with immune checkpoint blockers improved treatment outcomes in preclinical models, offering new therapeutic strategies.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Cancer cells evade immune detection via pathways like immune checkpoints.
- B7x (B7-H4, B7S1, VTCN1) is upregulated in advanced bladder cancer, but its role is unclear.
- PD-1/PD-L1 blockade offers limited durable responses (20-25%) in muscle-invasive bladder cancer (MIBC).
Purpose of the Study:
- To investigate the role of B7x in bladder cancer progression and immune evasion.
- To evaluate B7x as a therapeutic target to overcome resistance to immunotherapy.
Main Methods:
- Analysis of B7x mRNA and protein expression in MIBC patient data and bladder cancer mouse models.
- Assessment of tumor growth, immune cell infiltration, and splenomegaly in B7x-expressing mouse models.
- Evaluation of combination therapy targeting B7x with PD-1/PD-L1 or CTLA-4 blockade in preclinical models.
- Correlation analysis of B7x expression with survival outcomes in the IMvigor210 clinical trial.
Main Results:
- B7x expression correlated with poor survival in MIBC patients and mouse models.
- B7x promoted tumor growth and splenomegaly by suppressing antitumor immunity and enriching immunosuppressive cells.
- High B7x mRNA expression predicted poorer survival in MIBC patients treated with PD-L1 blockade.
- Combination therapy targeting B7x overcame resistance to PD-1/PD-L1 or CTLA-4 blockade, reducing tumor burden.
Conclusions:
- B7x is a significant driver of immune evasion in bladder cancer.
- Targeting B7x offers a promising strategy to enhance the efficacy of immune checkpoint blockade in MIBC.
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