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Updated: Jul 24, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma (mRCC) in Mice Following Nephrectomy
Published on: April 29, 2014
The T cell death knell: immune-mediated tumor death in renal cell carcinoma
R G Uzzo1, V Kolenko, C J Froelich
1Department of Immunology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. R_Uzzo@fccc.edu
Abstract:
The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.
Insights
T cells fight tumors via CD95 or Perforin/Granzyme B pathways. Renal cell carcinoma resists CD95 but undergoes necrosis via Perforin/Granzyme B, even without caspase activation.
Area of Science:
- Immunology and Cancer Biology
- Cell Death Mechanisms
Background:
- T cell-mediated antitumor immunity relies on CD95 or Perforin (PFN)/Granzyme B (GrB) pathways.
- Apoptosis induction typically requires caspase activation, but non-apoptotic cell death pathways are increasingly recognized.
Purpose of the Study:
- To investigate the roles of CD95 and PFN/GrB in mediating apoptosis and necrosis in human renal cell carcinoma (RCC).
- To explore caspase-independent cell death mechanisms in RCC.
Main Methods:
- Analysis of CD95 expression and apoptosis induction in human RCC.
- Assessment of PFN/GrB-mediated cytotoxicity.
- Measurement of caspase activity and FADD protein levels.
- Characterization of cell death morphology (apoptotic vs. necrotic).
Main Results:
- Human RCC expressed CD95 but was resistant to CD95-mediated apoptosis, linked to low FADD and caspase-3 activity.
- PFN/GrB-mediated cytotoxicity induced significant tumor cell death.
- Tumor cell death induced by PFN/GrB occurred independently of caspase activity.
- PFN/GrB-mediated cell death resulted in a high accumulation of necrotic cells.
Conclusions:
- Renal cell carcinoma exhibits resistance to CD95-induced apoptosis, suggesting evasion mechanisms.
- Perforin/Granzyme B pathway is a potent inducer of cell death in RCC, capable of bypassing caspase activation.
- PFN/GrB-mediated cytotoxicity leads to non-apoptotic necrosis in RCC, highlighting alternative cell death routes in cancer immunity.
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