Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity
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 C...
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| Format: | Article |
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American Association for Cancer Research
2016
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| Online Access: | https://eprints.nottingham.ac.uk/49781/ |
| _version_ | 1848798075839053824 |
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| author | Brentville, Victoria A. Metheringham, Rachael L. Gunn, Barbara Symonds, Peter Daniels, Ian Gijon, Mohamed Cook, Katherine Xue, Wei Durrant, Lindy |
| author_facet | Brentville, Victoria A. Metheringham, Rachael L. Gunn, Barbara Symonds, Peter Daniels, Ian Gijon, Mohamed Cook, Katherine Xue, Wei Durrant, Lindy |
| author_sort | Brentville, Victoria A. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:14:01Z |
| format | Article |
| id | nottingham-49781 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:14:01Z |
| publishDate | 2016 |
| publisher | American Association for Cancer Research |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-497812020-05-04T17:28:34Z https://eprints.nottingham.ac.uk/49781/ 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 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. American Association for Cancer Research 2016-02-01 Article PeerReviewed Brentville, Victoria A., Metheringham, Rachael L., Gunn, Barbara, Symonds, Peter, Daniels, Ian, Gijon, Mohamed, Cook, Katherine, Xue, Wei and Durrant, Lindy (2016) Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity. Cancer Research, 76 (3). pp. 548-560. ISSN 1538-7445 http://cancerres.aacrjournals.org/content/76/3/548 doi:10.1158/0008-5472.CAN-15-1085 doi:10.1158/0008-5472.CAN-15-1085 |
| spellingShingle | Brentville, Victoria A. Metheringham, Rachael L. Gunn, Barbara Symonds, Peter Daniels, Ian Gijon, Mohamed Cook, Katherine Xue, Wei Durrant, Lindy Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity |
| title | Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity |
| title_full | Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity |
| title_fullStr | Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity |
| title_full_unstemmed | Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity |
| title_short | Citrullinated vimentin presented on MHC-II in tumor cells is a target for CD4+ T-cell-mediated antitumor immunity |
| title_sort | citrullinated vimentin presented on mhc-ii in tumor cells is a target for cd4+ t-cell-mediated antitumor immunity |
| url | https://eprints.nottingham.ac.uk/49781/ https://eprints.nottingham.ac.uk/49781/ https://eprints.nottingham.ac.uk/49781/ |