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STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC
Shiyu Huang1,2, Xuke Qin1,2, Shujie Fu1,2
1Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
Abstract:
Kidney renal clear cell carcinoma (KIRC) is recognized as an immunogenic tumor, and immunotherapy is incorporated into its treatment landscape for decades. The acquisition of a tumor mesenchymal phenotype through epithelial-to-mesenchymal transition (EMT) is associated with immune evasion and can contribute to immunotherapy resistance. Here, the involvement of STAM Binding Protein Like 1 (STAMBPL1) is reported in the development of mesenchymal and immune evasion phenotypes in KIRC cells. Mechanistically, STAMBPL1 elevated protein abundance and surface accumulation of TAM Receptor AXL through diminishing the TRIM21-mediated K63-linked ubiquitination and subsequent lysosomal degradation of AXL, thereby enhancing the expression of mesenchymal genes while suppressing chemokines CXCL9/10 and HLA/B/C. In addition, STAMBPL1 enhanced PD-L1 transcription via facilitating nuclear translocation of p65, and knockdown (KD) of STAMBPL1 augmented antitumor effects of PD-1 blockade. Furthermore, STAMBPL1 silencing and the tyrosine kinase inhibitor (TKI) sunitinib also exhibited a synergistic effect on the suppression of KIRC. Collectively, targeting the STAMBPL1/TRIM21/AXL axis can decrease mesenchymal phenotype and potentiate anti-tumor efficacy of cancer therapy.
Insights
Targeting STAM Binding Protein Like 1 (STAMBPL1) can overcome immunotherapy resistance in kidney renal clear cell carcinoma (KIRC). STAMBPL1 promotes a mesenchymal phenotype and immune evasion, but its inhibition enhances anti-tumor effects and synergizes with sunitinib.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Kidney renal clear cell carcinoma (KIRC) is an immunogenic tumor where immunotherapy is a key treatment.
- Epithelial-to-mesenchymal transition (EMT) drives immune evasion and immunotherapy resistance in KIRC.
- STAM Binding Protein Like 1 (STAMBPL1) plays a role in KIRC's mesenchymal and immune evasion phenotypes.
Purpose of the Study:
- To investigate the role of STAMBPL1 in KIRC's mesenchymal and immune evasion phenotypes.
- To elucidate the mechanism by which STAMBPL1 influences KIRC progression and immune evasion.
- To evaluate STAMBPL1 as a therapeutic target for KIRC.
Main Methods:
- Investigated STAMBPL1's effect on mesenchymal gene expression and immune evasion markers.
- Analyzed STAMBPL1's regulation of TAM Receptor AXL via ubiquitination and lysosomal degradation.
- Assessed the impact of STAMBPL1 knockdown on PD-L1 expression and anti-tumor immunity.
- Evaluated the synergistic effect of STAMBPL1 silencing with sunitinib in KIRC.
Main Results:
- STAMBPL1 elevates AXL protein and surface accumulation by inhibiting TRIM21-mediated ubiquitination and degradation.
- STAMBPL1 enhances mesenchymal gene expression and suppresses immune-related chemokines (CXCL9/10) and HLA class I molecules.
- STAMBPL1 promotes PD-L1 transcription and nuclear translocation of p65, contributing to immune evasion.
- STAMBPL1 knockdown potentiates anti-PD-1 blockade efficacy and synergizes with sunitinib to suppress KIRC.
Conclusions:
- Targeting the STAMBPL1/TRIM21/AXL axis reduces the mesenchymal phenotype and immune evasion in KIRC.
- STAMBPL1 inhibition can enhance the efficacy of immunotherapy and chemotherapy in KIRC.
- STAMBPL1 represents a promising therapeutic target for overcoming immunotherapy resistance in KIRC.
