CD8+ T cells specific for the androgen receptor ar

Authors: Brian M Olson Douglas G McNeel

Publish Date: 2011/02/25

Volume: 60, Issue: 6, Pages: 781-792

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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 ligandbinding domain LBD as an immunological target seeking to identify HLAA2restricted epitopes recognized by T cells in prostate cancer patients Ten AR LBDderived HLAA2binding peptides were identified and ranked with respect to HLAA2 affinity and were used to culture peptidespecific T cells from HLAA2+ prostate cancer patients These Tcell cultures identified peptidespecific 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 Peptidespecific CD8+ Tcell clones were then isolated and characterized for prostate cancer cytotoxicity and cytokine expression identifying that AR805 and AR811 CD8+ Tcell clones could lyse prostate cancer cells in an HLAA2restricted fashion but only AR811 CTL had polyfunctional cytokine expression Epitopes were confirmed using immunization studies in HLAA2 transgenic mice in which the AR LBD is an autologous antigen with an identical protein sequence which showed that mice immunized with AR811 developed peptidespecific CTL that lyse HLAA2+ prostate cancer cells These data show that AR805 and AR811 are HLAA2restricted 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 antiprostate tumor immune response by augmenting CTL populations using AR LBDbased vaccinesThis work was supported for BMO and DGM by NIH K23 RR16489 and R01 CA142608 and the US Army Medical Research and Materiel Command DAMD W81XWH0710038 The authors would also like to thank Jordan Becker Edward Dunphy Thomas Frye and Laura Johnson for sera collection and peripheral blood mononuclear cell preparation We would also like to thank Dr François Lemonnier for his gracious provision of the A2/DR1 transgenic mice and Heath Smith for critical reading of the manuscript

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