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Cancer Res. 2016 Feb 1;76(3):548-60. doi: 10.1158/0008-5472.CAN-15-1085. Epub 2015 Dec 30.

Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity.

Author information

1
Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
2
Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom. Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom. lindy.durrant@nottingham.ac.uk.

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 IFN╬│- 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.

PMID:
26719533
DOI:
10.1158/0008-5472.CAN-15-1085
[Indexed for MEDLINE]
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