Title : Targeting HSD11B2–PD-L1 axis: A novel strategy to reverse immune escape and spontaneous metastasis in renal cell carcinoma
Abstract:
Background: Metastatic renal cell carcinoma (mRCC) remains a therapeutic challenge with poor prognosis, as current immunotherapy combinations often encounter resistance. Immune escape is a key driver of spontaneous metastasis; however, the underlying regulatory mechanisms in mRCC remain to be fully elucidated.
Purpose: This study aims to investigate the role of 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) in RCC spontaneous metastasis, clarify its regulatory network regarding immune escape, and evaluate the translational potential of HSD11B2-targeted therapy.
Methods: A spontaneous lung metastasis model of RCC was established via subcapsular injection of RENCA cells. Transcriptome sequencing identified HSD11B2 as a key downregulated molecule in metastatic foci. In vitro (MTT, Transwell, flow cytometry) and in vivo (subcutaneous xenograft, tail vein metastasis) experiments verified the function of HSD11B2. Co-IP, mass spectrometry, and ChIP assays explored interactions with PD-L1 and upstream regulation by the NR3C1/SP1/p300 complex. The therapeutic efficacy of the HSD11B2 activator, Isomaltotetraose (alone or combined with the PD-L1 inhibitor Lesabelimab), was evaluated in preclinical models.
Results: HSD11B2 was significantly downregulated in RCC metastatic tissues and cell lines (p<0.01). Knocking down HSD11B2 enhanced RCC cell invasion (2.3-fold vs. control, p<0.05) and lung metastasis (4.1-fold vs. control, p<0.01), while overexpression reversed these effects. Mechanistically, HSD11B2 bound to PD-L1 and promoted its ubiquitination and degradation via the ERAD pathway; consequently, downregulated HSD11B2 stabilized PD-L1, leading to reduced CD8+ T cell infiltration (38% decrease, p<0.05). Additionally, the NR3C1/SP1/p300 complex was found to suppress HSD11B2 transcription by inhibiting H3K27ac modification. Isomaltotetraose treatment reduced lung metastases by 52% (p<0.01), and its combination with Lesabelimab achieved a 76% reduction (p<0.001).
Conclusions: HSD11B2 downregulation promotes RCC spontaneous metastasis via PD-L1-mediated immune escape. The HSD11B2 activator Isomaltotetraose, particularly in combination with PD-L1 inhibitors, offers a novel therapeutic strategy for mRCC, aligning with the conference theme of transforming cancer care through innovative integrations.
