Durrant Lindy G, Metheringham Rachael L, Brentville Victoria A
a Academic Department of Clinical Oncology , Division of Cancer & Stem Cells, University of Nottingham , Nottingham , UK.
b Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham , Nottingham , UK.
Autophagy. 2016 Jun 2;12(6):1055-6. doi: 10.1080/15548627.2016.1166326. Epub 2016 May 4.
A cell needs to maintain a balance between biosynthesis and degradation of cellular components to maintain homeostasis. There are 2 pathways, the proteasome, which degrades short-lived proteins, and the autophagy/lysosomal pathway, which degrades long-lived proteins and organelles. Both of these pathways are also involved in antigen presentation or the effective delivery of peptides to MHC molecules for presentation to T cells. Autophagy (macroautophagy) is a key player in providing substantial sources of citrullinated peptides for loading onto MHC-II molecules to stimulate CD4(+) T cell responses. Stressful conditions in the tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. We therefore investigated if citrullinated peptides could stimulate CD4(+) T cell responses that would recognize these modifications produced during autophagy within tumor cells. Focusing on the intermediate filament protein VIM (vimentin), we generated citrullinated VIM peptides for immunization experiments in mice. Immunization with these peptides induced CD4(+) T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 d after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. 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 produced during autophagy may offer especially attractive vaccine targets for cancer therapy.
细胞需要在细胞成分的生物合成和降解之间保持平衡以维持体内稳态。有两条途径，即蛋白酶体途径（降解短寿命蛋白质）和自噬/溶酶体途径（降解长寿命蛋白质和细胞器）。这两条途径也都参与抗原呈递或肽向MHC分子的有效递送以呈递给T细胞。自噬（巨自噬）在提供大量瓜氨酸化肽以加载到MHC-II分子上以刺激CD4(+) T细胞反应方面起着关键作用。肿瘤微环境中的应激条件会诱导癌细胞自噬，作为促进其存活的一种机制。因此，我们研究了瓜氨酸化肽是否能刺激CD4(+) T细胞反应，该反应能识别肿瘤细胞自噬过程中产生的这些修饰。聚焦于中间丝蛋白波形蛋白（VIM），我们制备了瓜氨酸化的VIM肽用于小鼠免疫实验。用这些肽进行免疫可诱导CD4(+) T细胞对自噬性肿瘤靶标产生反应。值得注意的是，在肿瘤植入后长达14天，用修饰肽进行单次免疫可使60%至90%的动物长期存活且无相关毒性。这些结果表明CD4(+)细胞如何介导针对肿瘤细胞上呈现的修饰自身表位的有效抗肿瘤反应，并且它们首次说明了自噬过程中产生的瓜氨酸化肽可能为癌症治疗提供特别有吸引力的疫苗靶点。
