CD4 cells are potent effectors but CD4 responses to tumour associated antigens are attenuated. Cellular stress induces autophagy which leads to modification of proteins recognised by the immune system. In the absence of inflammation, immunity is regulated, whereas in its presence CD4 responses to modified self-antigens are stimulated. T cells commonly target modified self-antigens and have been shown to play a role in the pathophysiology of several autoimmune diseases. In this study the ability of these CD4 cells to target cancer has been explored. One modification is conversion of arginine to citrulline. Peptidylarginine deiminases (PADs), are a family of calcium dependent enzymes found in a variety of tissues, where their role is post translation citrullination of proteins. Citrullination is conversion of the positively charge aldimine group ( = NH) group of arginine to the neutrally charged ketone group ( = O) of citrulline. Immunisation with citrullinated vimentin peptides induced IFNγ and granzyme B secreting CD4 T cells in response to autophagic tumour targets. The induced CD4 responses to citrullinated self-peptide epitopes show minimal reactivity to the unmodified sequence. A single immunization with modified peptide, up to 14 days after tumour implant, resulted in long term survival in 60-90% of animals with no associated toxicity. The anti-tumour responses were dependent upon CD4 but not on CD8 T cells. This study provides the first evidence that tumours can present citrullinated peptides that can be targets for CD4 cells. This presentation is dependent upon autophagy and PAD enzymes. The CD4 T cells release IFNγ and show direct cytotoxicity which results in potent anti-tumour responses in vivo. This approach is being fast tracked into the clinic in patient's whose tumours express vimentin. This could be patients with mesenchymal tumours or in patients whose tumours undergo epithelial to mesenchymal transition as vimentin is one of the first proteins to be expressed in this transition.
Citation Format: Lindy G. Durrant, Victoria A. Brentville, Rachael L. Metheringham, Ian Daniels, Peter Symonds, Mohamed Gijon, Wei Xue. CD4 T cells targeting citrullinated vimentin reject advanced tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1348. doi:10.1158/1538-7445.AM2015-1348