Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity

Brentville, Victoria A.; Metheringham, Rachael L.; Gunn, Barbara; Symonds, Peter; Daniels, Ian; Gijon, Mohamed; Cook, Katherine; Xue, Wei; Durrant, Lindy

Abstract

Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4(+) T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-to-mesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFNγ- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8(+) T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy.

Citation

Brentville, V. A., Metheringham, R. L., Gunn, B., Symonds, P., Daniels, I., Gijon, M., …Durrant, L. (2016). Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity. Cancer Research, 76(3), 548-560. https://doi.org/10.1158/0008-5472.CAN-15-1085

• Journal Article Type: Article
• Acceptance Date: Nov 21, 2015
• Online Publication Date: Dec 30, 2015
• Publication Date: Feb 1, 2016
• Deposit Date: Feb 14, 2018
• Publicly Available Date: Feb 14, 2018
• Journal: Cancer Research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 76
• Issue: 3
• Pages: 548-560
• DOI: https://doi.org/10.1158/0008-5472.CAN-15-1085
• Public URL: https://nottingham-repository.worktribe.com/output/770534
• Publisher URL: http://cancerres.aacrjournals.org/content/76/3/548
• Additional Information: Supplementary data for this article are available at Cancer Research; Online (http://cancerres.aacrjournals.org/content/suppl/2015/12/30/0008-5472.CAN-15-1085.DC1.html).; ; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.