Targeting HLA-E for prostate cancer immunotherapy

Abstract

Abstract Genetically modified strain 68-1 rhesus cytomegalovirus (RhCMV)-derived vaccine vectors uniquely elicit CD8+ T cells recognizing peptides presented by non-polymorphic MHC-E instead of conventional MHC-I molecules. Since MHC-E (HLA-E in humans) is a ligand for inhibitory receptors on NK cells, the upregulation of MHC-E is a known immune evasion strategy for both cancers and intracellular pathogens. Indeed, using tissue arrays we observed that early stage prostate cancer tissues express high levels of HLA-E, as shown by immunohistochemistry, whereas healthy prostate samples were negative. To determine whether MHC-E-restricted T cells recognizing prostate antigens could be used to target prostate cancer we inserted rhesus prostatic acid phosphatase (rhPAP) into RhCMV. Upon inoculation of rhesus macaques (RM) we observed a T cell response comparable to heterologous antigens suggesting that CMV-based vectors excel at eliciting T cell responses to tumor antigens, including self-antigens. Furthermore, all CD8+ T cells recognized rhPAP either in the context of MHC-II or MHC-E, but not MHC-I. Importantly, MHC-E-restricted CD8+ T cells recognized PAP and MHC-E-expressing K562 cells suggesting that endogenous PAP-derived peptides can be loaded onto MHC-E. We further demonstrate that PAP and HLA-E-positive human prostate adenocarcinoma cells stimulated PAP-specific rhesus CD8+ T cells restricted by MHC-E. We conclude that prostate cancer cells load highly conserved HLA-E molecules with prostate antigen-derived peptides that can be targeted by HLA-E-restricted CD8+ T cells thus exploiting a previously unexplored immunological vulnerability.