CD8+ T cells specific for the androgen receptor are common in patients with prostate cancer and are able to lyse prostate tumor cells
- 25 February 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 60 (6), 781-792
- https://doi.org/10.1007/s00262-011-0987-5
Abstract
The androgen receptor (AR) is a hormone receptor that plays a critical role in prostate cancer, and depletion of its ligand has long been the cornerstone of treatment for metastatic disease. Here, we evaluate the AR ligand-binding domain (LBD) as an immunological target, seeking to identify HLA-A2-restricted epitopes recognized by T cells in prostate cancer patients. Ten AR LBD-derived, HLA-A2-binding peptides were identified and ranked with respect to HLA-A2 affinity and were used to culture peptide-specific T cells from HLA-A2+ prostate cancer patients. These T-cell cultures identified peptide-specific T cells specific for all ten peptides in at least one patient, and T cells specific for peptides AR805 and AR811 were detected in over half of patients. Peptide-specific CD8+ T-cell clones were then isolated and characterized for prostate cancer cytotoxicity and cytokine expression, identifying that AR805 and AR811 CD8+ T-cell clones could lyse prostate cancer cells in an HLA-A2-restricted fashion, but only AR811 CTL had polyfunctional cytokine expression. Epitopes were confirmed using immunization studies in HLA-A2 transgenic mice, in which the AR LBD is an autologous antigen with an identical protein sequence, which showed that mice immunized with AR811 developed peptide-specific CTL that lyse HLA-A2+ prostate cancer cells. These data show that AR805 and AR811 are HLA-A2-restricted epitopes for which CTL can be commonly detected in prostate cancer patients. Moreover, CTL responses specific for AR811 can be elicited by direct immunization of A2/DR1 mice. These findings suggest that it may be possible to elicit an anti-prostate tumor immune response by augmenting CTL populations using AR LBD-based vaccines.Keywords
This publication has 46 references indexed in Scilit:
- Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate CancerJournal of Clinical Oncology, 2010
- HLA-A2-restricted T-cell epitopes specific for prostatic acid phosphataseCancer Immunology, Immunotherapy, 2010
- Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate CancerJournal of Clinical Oncology, 2009
- Treatment-Dependent Androgen Receptor Mutations in Prostate Cancer Exploit Multiple Mechanisms to Evade TherapyCancer Research, 2009
- Self-antigen–specific CD8+ T cell precursor frequency determines the quality of the antitumor immune responseThe Journal of Experimental Medicine, 2009
- Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate CancerCancer Research, 2008
- CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefitProceedings of the National Academy of Sciences of the United States of America, 2008
- Polyfunctional T cell responses are a hallmark of HIV‐2 infectionEuropean Journal of Immunology, 2008
- Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responsesThe Journal of Experimental Medicine, 2007
- Androgen receptor gene amplification and protein expression in hormone refractory prostate cancerBritish Journal of Cancer, 2003