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APOL6 predicts immunotherapy efficacy of bladder cancer by ferroptosis
Zhiwei Fan1,2,3, Yiting Liu1,2,4, Xuehai Wang2
1Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226006, China.
Background:
Immune checkpoint inhibitors (ICIs) are rapidly evolving in the management of bladder cancer (BLCA). Nevertheless, effective biomarkers for predicting immunotherapeutic outcomes in BLCA are still insufficient. Ferroptosis, a form of immunogenic cell death, has been found to enhance patient sensitivity to ICIs. However, the underlying mechanisms of ferroptosis in promoting immunotherapy efficacy in BLCA remain obscure.
Methods:
Our analysis of The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) revealed two immunologically distinct subtypes. Based on these subtypes and various other public cohorts, we identified Apolipoprotein L6 (APOL6) as a biomarker predicting the efficacy of ICIs and explored its immunological correlation and predictive value for treatment. Furthermore, the role of APOL6 in promoting ferroptosis and its mechanism in regulating this process were experimentally validated.
Results:
The results indicate that APOL6 has significant immunological relevance and is indicative of immunologically hot tumors in BLCA and many other cancers. APOL6, interacting with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), mediates immunotherapy efficacy by ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1).
Conclusions:
To conclude, our findings indicate APOL6 has potential as a predictive biomarker for immunotherapy treatment success estimation and reveal the STAT1/APOL6/GPX4 axis as a critical regulatory mechanism in BLCA.
Insights
Apolipoprotein L6 (APOL6) shows promise as a biomarker for predicting bladder cancer immunotherapy success. It mediates efficacy through ferroptosis, offering new insights into treatment response.
Area of Science:
- Oncology
- Immunology
- Cancer Genomics
Background:
- Immune checkpoint inhibitors (ICIs) are crucial for bladder cancer (BLCA) treatment, but predictive biomarkers are lacking.
- Ferroptosis, a form of cell death, can enhance ICI sensitivity, yet its role in BLCA immunotherapy is unclear.
Purpose of the Study:
- Identify novel biomarkers for predicting immunotherapy response in BLCA.
- Elucidate the role of ferroptosis in mediating immunotherapy efficacy.
- Investigate the regulatory mechanisms of ferroptosis in BLCA.
Main Methods:
- Analyzed TCGA mRNA data using ssGSEA to identify distinct immune subtypes.
- Identified Apolipoprotein L6 (APOL6) as a potential biomarker across multiple cohorts.
- Experimentally validated the role of APOL6 in ferroptosis and its mechanism.
Main Results:
- APOL6 is immunologically relevant and predicts "hot" tumors in BLCA and other cancers.
- APOL6 interacts with ACSL4 to mediate immunotherapy efficacy via ferroptosis.
- STAT1 regulates APOL6, forming a key signaling axis.
Conclusions:
- APOL6 shows potential as a predictive biomarker for immunotherapy success in BLCA.
- The STAT1/APOL6/GPX4 axis is a critical regulatory mechanism in BLCA immunotherapy.
- Understanding this axis may improve treatment strategies.
