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IL15 can reverse the unresponsiveness of Wilms' tumor antigen-specific CTL in patients with prostate cancer
Judy W King1, Sharyn Thomas, Fabrizio Corsi
1Department of Immunology, University College London, Royal Free Hospital, London, United Kingdom.
Purpose:
The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients.
Experimental Design:
Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro.
Results:
Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2-positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNgamma production of WT1-specific T cells in a subgroup of prostate cancer patients.
Conclusion:
The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.
Insights
Wilms' tumor antigen 1 (WT1) is present in prostate cancer. Interleukin 15 (IL15) can restore the function of WT1-specific T cells, offering potential for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Wilms' tumor antigen 1 (WT1) is overexpressed in various cancers.
- Its role in prostate cancer and associated T-cell responses remains largely unexplored.
Purpose of the Study:
- To investigate WT1 expression in prostate cancer tissues.
- To determine the frequency and function of WT1-specific T cells in patients' peripheral blood.
Main Methods:
- Immunohistochemistry to detect WT1 expression in 36 cancer and 8 normal prostate samples.
- Human leukocyte antigen A2 (HLA-A2) tetramer analysis to identify WT1-specific T cells.
- In vitro T-cell stimulation assays using various cytokines (IL2, IL7, IL15).
Main Results:
- Nuclear WT1 staining was observed in 39% of prostate cancer samples, absent in normal tissues.
- A low frequency of WT1-specific T cells was detected in HLA-A2-positive patients.
- Interleukin 15 (IL15) restored expansion and IFN-gamma production of WT1-specific T cells, unlike IL2/IL7.
Conclusions:
- WT1 is expressed in prostate cancer, and WT1-specific T cells exist but may be functionally impaired.
- IL15 demonstrates potential in overcoming T-cell unresponsiveness, suggesting novel immunotherapeutic strategies for prostate cancer.
