Background: The ability to generate potent anti-tumor CTL responses is fundamental to the rejection of many tumors. However many potent anti-tumor responses are suppressed by regulatory T cells (Treg) preventing this. Recent clinical trial studies, using checkpoint inhibitors have shown great promise in inducing protective anti-tumor responses albeit in a minority of patients. In the mouse CT26 tumor model, removal of Treg suppression uncovers potent cryptic anti-GSW11 CTL, which are immunodominant and protective. The generation of GSW11 peptide in the ER is susceptible to destruction by endoplasmic reticulum aminopeptidase 1 (Erap1) significantly reducing the amount presented at the cell surface to T cells. Here we investigate the ability to overcome Treg suppression by modulating the function of Erap1.
Methods: GSW11-specific T cells were characterised from CT26 challenged Treg replete and depleted mice by flow cytometry. Attenuation of Erap1 function was achieved using either the inhibitor Leucine-thiol or siRNA and its effect on GSW11 generation determined by T cell activation assays and reverse phase HPLC.
Results: We identified that Treg suppressed GSW11-specific T cells exhibit a clonally exhausted phenotype in CT26 challenged mice. Examination of GSW11 peptide generation showed that attenuation of Erap1 function by inhibition or siRNA significantly increased the generation of GSW11 (∼75-fold increase). Strikingly, Treg replete mice challenged with Erap1 siRNA CT26 were able overcome Treg suppression and induce GSW11-specific T cell responses resulting in tumor protection. In addition, in vivo intra-tumoral administration of Erap1 inhibitor in established CT26 tumors resulted in the attenuation or regression of tumor growth in the majority of mice.
Conclusions: These results reveal the therapeutic potential of modulating Erap1 function to alter tumor-specific antigen presentation to overcome clonal exhaustion and generate potent anti-tumor T cell immunity.
Citation Format: Gessa Sugiyarto, Ian Bailey, Tim Elliott, Edward James. Induction of protective antitumor immunity through attenuation of endoplasmic reticulum aminopeptidase 1 function [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B064.
- ©2016 American Association for Cancer Research.