PDF(Pubmed)
Abstract：
Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells\' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.
摘要：
胰腺癌是一种致命的疾病,5年总生存率仅为13%。因此，当前的治疗方法需要调制，随着注意力转向释放免疫疗法停滞不前的功效。选择具有固有免疫修饰行为的化疗药物可以恢复针对胰腺肿瘤的免疫活性并增强免疫治疗的成功。在这项研究中,我们描述了吉西他滨的影响，一种被批准用于治疗胰腺癌的化疗药物，关于人类白细胞抗原I类（HLA-I）的肿瘤抗原呈递。吉西他滨增加胰腺癌细胞HLA-ImRNA转录本，总蛋白质，表面表达式,表面稳定性。温度依赖性测定结果表明,增加的HLA-I稳定性可能是由于低亲和力肽的结合减少。质谱分析证实了治疗后HLA-I呈递肽库的变化，和计算预测表明，仅通过吉西他滨处理的细胞显示的肽的亲和力和免疫原性得到改善。大多数吉西他滨专有肽来自独特的来源蛋白，与翻译相关的蛋白质有明显的过度表达。吉西他滨也增加了选择的免疫蛋白酶体亚基的表达，提供了一种合理的机制来调节HLA-I结合的肽组。我们的工作支持免疫疗法的持续研究，包括基于肽的疫苗，与吉西他滨一起用作胰腺癌的新联合治疗方式。
