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Published on: April 28, 2013
TGF-alpha as a candidate tumor antigen for renal cell carcinomas
Sandy Pelletier1, Simon Tanguay, Stephen Lee
1Department of Medicine, CRCHUM-Hôpital Notre-Dame, Université de Montréal, Montreal, Canada.
Objectives:
Patients with renal cell carcinomas (RCC) have few treatment options, underscoring the importance of developing new approaches such as immunotherapy. However, few tumor associated antigens (TAA), which can be targeted by immunotherapy, have been identified for this type of cancer. von Hippel-Lindau clear cell RCC (VHL(-/-)RCC) are characterized by mutations in the VHL tumor suppressor gene. Loss of VHL function causes the overexpression of transforming growth factor (TGF)-alpha, leading us to hypothesize that TGF-alpha could be a potential TAA for immunotherapy of kidney cancer, which was evaluated in this study.
Methods And Results:
We first confirmed the absent or weak expression of TGF-alpha in important normal tissues as well as its overexpression in 61% of renal tumors in comparison to autologous normal kidney tissues. In addition, we demonstrated the immunogenicity of TGF-alpha, by expanding many T cell lines specific for certain TGF-alpha peptides or the mature TGF-alpha protein, when presented by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells. Interestingly, some of these TGF-alpha-specific T cells were polyfunctionals and secreted IFN-gamma, TNF-alpha and IL-2.
Conclusion:
We have shown that TGF-alpha is a valid candidate TAA, which should allow the development of a targeted immunotherapy.
Insights
Transforming growth factor-alpha (TGF-alpha) shows promise as a tumor associated antigen (TAA) for kidney cancer immunotherapy. This study identified TGF-alpha overexpression in renal tumors and demonstrated its immunogenicity, supporting its potential as a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Renal cell carcinoma (RCC) presents limited therapeutic options, necessitating novel treatment strategies like immunotherapy.
- Identifying suitable tumor associated antigens (TAAs) is crucial for effective cancer immunotherapy.
- Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene characterize VHL(-/-)RCC, leading to transforming growth factor-alpha (TGF-alpha) overexpression.
Purpose of the Study:
- To evaluate TGF-alpha as a potential TAA for immunotherapy in kidney cancer.
- To investigate the expression patterns of TGF-alpha in normal kidney tissues versus renal tumors.
- To assess the immunogenicity of TGF-alpha and its capacity to elicit T cell responses.
Main Methods:
- Quantitative analysis of TGF-alpha expression in normal and cancerous kidney tissues.
- Generation and characterization of T cell lines specific for TGF-alpha peptides and mature protein.
- Assessment of T cell functionality, including cytokine secretion (IFN-gamma, TNF-alpha, IL-2).
Main Results:
- TGF-alpha was found to be weakly or absent in normal tissues but overexpressed in 61% of renal tumors.
- Immunogenicity of TGF-alpha was confirmed through the expansion of specific T cell lines.
- A subset of TGF-alpha-specific T cells exhibited polyfunctionality, secreting key immune-activating cytokines.
Conclusions:
- TGF-alpha is a validated candidate TAA for kidney cancer.
- The findings support the development of TGF-alpha-targeted immunotherapies for renal cell carcinoma.
