Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma

Area of Science:

• Oncology
• Immunology
• Tumor Microenvironment

Background:

• Clear cell renal cell carcinoma (ccRCC) exhibits a pseudohypoxic state, making it responsive to vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and anti-PD-1 (aPD-1) therapies.
• While combination therapies improve outcomes, their long-term durability is less than dual anti-PD-1/anti-CTLA-4 regimens, and the underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the evolution of the tumor microenvironment in response to VEGFR-TKI, aPD-1, and combined VEGFR-TKI/aPD-1 treatments in a ccRCC mouse model.
• To identify biomarkers predicting response and understand the paradoxical role of hypoxia in ccRCC treatment outcomes.

Main Methods:

• Utilized a transgenic ccRCC mouse model for in vivo studies.
• Employed single-cell RNA sequencing and imaging mass cytometry on mouse and human cohorts.
• Analyzed pretreatment and on-treatment tumor samples to assess microenvironment changes.

Main Results:

• Identified hypoxia-responsive SPP1+ tumor-associated macrophages (TAMs) as a marker of successful VEGFR-TKI/aPD-1 therapy, reflecting treatment-induced hypoxic necrosis.
• Observed that pretreatment hypoxia predicted worse outcomes in VEGFR-TKI/aPD-1 trials and real-world ccRCC patient data.
• Demonstrated that prolonged VEGFR-TKI exposure exacerbated metastasis in mice, indicating a detrimental role of sustained hypoxia.

Conclusions:

• SPP1+ TAMs serve as a predictive biomarker for response to combined VEGFR-TKI/aPD-1 therapy in ccRCC.
• Hypoxia plays a complex, dual role in ccRCC, with pretreatment hypoxia and VEGFR-TKI-induced hypoxia negatively impacting prognosis and potentially promoting metastasis.