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Published on: October 30, 2013
METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation
Yonghua Tong1, Zhiqiang Chen1, Jian Wu1
1Department of Urology, Huazhong University of Science and Technology, Wuhan, China.
Background:
Bladder cancer (BLCA) is a challenging malignancy with a poor prognosis, particularly in muscle-invasive cases. Despite recent advancements in immunotherapy, response rates remain suboptimal. This study investigates the role of METTL3, an m6A RNA methylation "writer," in regulating the immune microenvironment of BLCA.
Methods:
Through bioinformatics analysis, we identified METTL3 as being associated with the formation of an immunosuppressive microenvironment in BLCA and poor response to immunotherapy. Subsequently, we silenced METTL3 expression in BLCA cells using short hairpin RNA (shRNA) or inhibited its function with STM2457. The effectiveness of these interventions in remodeling the BLCA tumor microenvironment (TME) was confirmed through animal experiments and flow cytometry. Mechanistically, RNA sequencing and methylated RNA immunoprecipitation (MeRIP) sequencing revealed the molecular pathways by which METTL3 regulates the TME. This was further validated using in vitro cell co-culture, immunoprecipitation, ELISA, and RNA degradation assays. The synergistic effect of METTL3 with anti-Programmed Cell Death Protein 1 (PD-1) treatment in BLCA was confirmed in both orthotopic and ectopic BLCA animal models.
Results:
METTL3 was found to increase CXCL5 levels and suppress CCL5 expression in an m6A-dependent manner, leading to increased recruitment of myeloid-derived suppressor cells (MDSCs) and reduced infiltration of CD8+T cells. Silencing METTL3 or inhibiting its function restored immune cell balance and significantly enhanced the efficacy of anti-PD-1 therapy. Clinically, METTL3 overexpression correlated with poor complete response rate to immune checkpoint inhibitors (ICIs) therapy, associated with an immunosuppressive microenvironment characterized by elevated MDSC levels and reduced CD8+T cell infiltration.
Conclusions:
These findings highlight METTL3 as a key regulator of the immune microenvironment in BLCA and a promising therapeutic target to improve immunotherapy outcomes. Targeting METTL3 could potentially enhance the efficacy of ICIs in patients with BLCA.
Insights
Targeting METTL3, an RNA methylation enzyme, can overcome resistance to immunotherapy in bladder cancer (BLCA). Inhibiting METTL3 restores anti-tumor immunity by reducing immunosuppressive cells and increasing T cell infiltration, improving treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Bladder cancer (BLCA) presents a significant clinical challenge with poor prognoses, especially in muscle-invasive stages.
- Current immunotherapies offer suboptimal response rates, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of METTL3 (an m6A RNA methylation writer) in shaping the immune microenvironment of BLCA.
- To explore METTL3 as a potential therapeutic target for enhancing immunotherapy efficacy in BLCA.
Main Methods:
- Bioinformatic analysis identified METTL3's association with an immunosuppressive BLCA microenvironment.
- METTL3 was silenced or inhibited in BLCA cells, with effects on the tumor microenvironment (TME) assessed via animal models and flow cytometry.
- RNA sequencing and MeRIP sequencing elucidated METTL3's regulatory mechanisms within the TME.
Main Results:
- METTL3 overexpression promotes an immunosuppressive TME by increasing CXCL5 and decreasing CCL5, leading to higher myeloid-derived suppressor cell (MDSC) recruitment and lower CD8+T cell infiltration.
- METTL3 inhibition or silencing reversed these effects, restoring immune balance and significantly enhancing anti-PD-1 therapy efficacy.
- Clinically, high METTL3 levels correlated with poor response to immune checkpoint inhibitors (ICIs) and an immunosuppressive TME.
Conclusions:
- METTL3 is a critical regulator of the BLCA immune microenvironment.
- Targeting METTL3 represents a promising strategy to improve immunotherapy outcomes for bladder cancer patients.
