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Updated: Jul 3, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Targeting oxidative phosphorylation to increase the efficacy of immune-combination therapy in renal cell carcinoma
Jihua Tian1,2, Jing Luo3, Xing Zeng1
1Department of Urology, Tongji Hospital Affiliated Tongji Medical College of Huazhong University of Science and Technology (HUST), Wuhan, China.
Background:
Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic renal cell carcinoma (RCC); however, most patients develop de novo or acquired resistance to ICIs. Oxidative phosphorylation (OXPHOS) has been rarely explored as a potential target for correcting ICI resistance.
Methods:
We systematically analyzed RNA sequencing and clinical data from CheckMate, JAVELIN Renal 101, and NCT01358721 clinical trials, and clinicopathological data of 25 patients from Tongji Hospital to investigate the relationship between OXPHOS and ICI resistance. The Ndufb8-knockdown Renca cell line was derived to determine the effect of OXPHOS on RCC immunotherapy in vivo.
Results:
An analysis of the CheckMate series data revealed that high OXPHOS levels are risk factors for ICI in patients with RCC, but are affected by thevon Hippel-Lindau protein (VHL) and hypoxia-inducible factor-1α status. This result is consistent with correlation between clinicopathological characteristics and prognostic observations at our institute. Knockdown of the mitochondrial complex I subunit Ndufb8 of the Renca cell line had no effect on cell growth and migration in vitro, but slowed down cell growth in vivo. Among anti-programmed death ligand 1 (PD-L1)-treated BALB/c mice, shNdufb8 Renca tumors grew slower than shControl Renca tumors and the corresponding mice survived longer. Flow cytometry revealed that CD8+ T cells in shNdufb8 Renca tumors, which were exposed to a lower degree of hypoxia and expressed less programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3), secreted more interferon-γ after stimulation. Immunofluorescence demonstrated that the shNdufb8 Renca tumors had a higher proportion of CD8+ T cells and the proportion of these cells was lower in the hypoxic area.
Conclusions:
OXPHOS is a reliable predictor of immunotherapy response in RCC and is more pronounced in metastatic lesions. RCC cells generate a hypoxic tumor microenvironment and inhibit T-cell function through oxidative metabolism, thereby leading to immunotherapy resistance.
Insights
High oxidative phosphorylation (OXPHOS) levels predict resistance to immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC). Targeting OXPHOS may improve immunotherapy response by enhancing T-cell function in the tumor microenvironment.
Area of Science:
- Immunology
- Oncology
- Metabolism
Background:
- Immune checkpoint inhibitors (ICIs) are standard treatment for metastatic renal cell carcinoma (RCC).
- Most patients develop resistance to ICIs, necessitating novel therapeutic strategies.
- Oxidative phosphorylation (OXPHOS) has not been extensively studied as a target for overcoming ICI resistance.
Purpose of the Study:
- To investigate the relationship between OXPHOS and ICI resistance in RCC.
- To explore OXPHOS as a potential target to enhance immunotherapy efficacy in RCC.
Main Methods:
- Systematic analysis of RNA sequencing and clinical data from multiple RCC clinical trials.
- Analysis of clinicopathological data from RCC patients at Tongji Hospital.
- In vivo study using an Ndufb8-knockdown Renca cell line to assess OXPHOS's role in RCC immunotherapy.
Main Results:
- High OXPHOS levels were identified as a risk factor for ICI resistance in RCC, influenced by VHL and HIF-1α status.
- Ndufb8 knockdown in Renca cells slowed tumor growth in vivo and improved survival in mice treated with anti-PD-L1 therapy.
- Reduced OXPHOS in tumors correlated with increased CD8+ T cell infiltration, reduced hypoxia, and enhanced anti-tumor immune responses (lower PD-1/TIM-3 expression, higher IFN-γ secretion).
Conclusions:
- OXPHOS is a reliable predictor of immunotherapy response in RCC, particularly in metastatic lesions.
- RCC cells utilize oxidative metabolism to create a hypoxic tumor microenvironment, suppressing T-cell function and causing ICI resistance.
- Targeting OXPHOS may represent a viable strategy to overcome ICI resistance in RCC.
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