Abstract B102: Pre-existing citrulline-specific CD4 T-cells can be efficiently harnessed for tumor therapy

Abstract

Citrullination is the post-translational modification of arginine to citrulline mediated by Peptidylarginine deiminases (PADs), which are a family of calcium dependent enzymes found in a variety of tissues. Citrullinated proteins are known to play a significant role in the pathogenesis of autoimmune diseases and are presented in complex with MHC class II. We have previously shown that citrullinated peptides from vimentin and α-enolase are presented on HLA-DR4 in tumor cells and mediate strong anti-tumor responses (Brentville et al., 2016; Cook et al., 2017). Here we show that responses to these peptides are also restricted through HLA-DP4. These responses can be detected within 2 days of vaccination and can mediate rapid regression of tumors within 4 days in mice suggesting evidence of a pre-existing repertoire of T-cells specific for these citrullinated peptides. Evidence of CD4 T-cells specific to citrullinated antigens have been identified in a number of autoimmune disease patients in particular rheumatoid arthritis patients. These patients show an increase in frequency and change in phenotype of citrulline specific CD4 T-cells compared to healthy individuals (James et al., 2014). In this report we also demonstrate that a repertoire of CD4 T-cell responses to citrullinated peptides exists in healthy individuals and that this can be uncovered/enhanced by removal of CD25+ T-cells thus suggesting the existence of a regulatory mechanism keeping these responses in check. The responding populations appear to be oligoclonal and show an increase in effector memory and Temra phenotype. This suggests that a repertoire of CD4 T-cells exists to citrullinated peptides that could be targeted for cancer therapy. Citation Format: Victoria A. Brentville, Peter Symonds, Katherine W. Cook, Ian Daniels, Suha Atabani, Ruhul Choudhury, Poonam Vaghela, Rachael L. Metheringham, Mohamed Gijon, Wei Xue, Lindy G. Durrant. Pre-existing citrulline-specific CD4 T-cells can be efficiently harnessed for tumor therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B102.