Gravett A M, Trautwein N, Stevanović S, Dalgleish A G, Copier J
Institute for infection and immunity, St George's, University of London, London, UK.
Department of Immunology, Institute of Cell Biology, University of Tübingen, Tübingen, Germany.
Oncoimmunology. 2018 Mar 6;7(6):e1438107. doi: 10.1080/2162402X.2018.1438107. eCollection 2018.
The antigenic makeup of tumour cells can have a profound effect on the progression of cancer and success of immunotherapies. Therefore, one strategy to improve the efficacy of cancer treatments is to augment the antigens displayed by tumours. The present study explores how the recognition of tumour cells may be altered by non-cytotoxic concentrations of gemcitabine (GEM). Testing a panel of chemotherapeutics in human cancer cell lines , it was found that GEM increased surface expression of HLA-A,B,C and that underlying this were specific increases in β-2-microglobulin and immunoproteasome subunit proteins. Furthermore, the peptide antigen repertoire displayed on HLA class I was altered, revealing a number of novel antigens, many of which that were derived from proteins involved in the DNA-damage response. Changes in the nature of the peptide antigens eluted from HLA-A,B,C after GEM treatment consisted of amino acid anchor-residue modifications and changes in peptide length which rendered peptides likely to favour alternative HLA-alleles and increased their predicted immunogenicity. Signalling through the MAPK/ERK and NFκB/RelB pathways was associated with these changes. These data may explain observations made in previous studies, advise as to which antigens should be used in future vaccination protocols and reinforce the idea that chemotherapy and immunotherapy could be used in combination.
肿瘤细胞的抗原组成可对癌症进展和免疫疗法的成效产生深远影响。因此，提高癌症治疗效果的一种策略是增加肿瘤所展示的抗原。本研究探讨了非细胞毒性浓度的吉西他滨（GEM）如何改变对肿瘤细胞的识别。在人癌细胞系中测试一组化疗药物时，发现GEM增加了HLA-A、B、C的表面表达，其背后是β-2-微球蛋白和免疫蛋白酶体亚基蛋白的特异性增加。此外，HLA I类分子上展示的肽抗原库发生了改变，揭示了一些新抗原，其中许多源自参与DNA损伤反应的蛋白质。GEM处理后从HLA-A、B、C洗脱的肽抗原性质的变化包括氨基酸锚定残基修饰和肽长度的改变，这使得肽可能更倾向于替代HLA等位基因并增加其预测的免疫原性。通过MAPK/ERK和NFκB/RelB途径的信号传导与这些变化相关。这些数据可能解释了先前研究中的观察结果，为未来疫苗接种方案中应使用哪些抗原提供建议，并强化了化疗和免疫疗法可联合使用的观点。
