title: Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity.
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.
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Brentville
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Metheringham
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gunn
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Symonds
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Daniels
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Gijon
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Cook
authors.affiliation: Scancell Limited Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, United Kingdom.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: 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.
authors.forename: Lindy G
authors.initials: LG
authors.lastname: Durrant
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002956:Citrulline / Q000276:immunology / Q000378:metabolism; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D057809:HEK293 Cells; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology*; D011897:Random Allocation; D014162:Transfection; D014746:Vimentin / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018985:Epitopes, B-Lymphocyte; D015804:HLA-DR4 Antigen; D010446:Peptide Fragments; D014746:Vimentin; D002956:Citrulline