Abstract：
Conventional treatments have shown a limited efficacy for pancreatic cancer, and immunotherapy is an emerging option for treatment of this highly fatal malignancy. Neoantigen is critical to improving the efficacy of tumor-specific immunotherapy. The cancer and peripheral blood specimens from an HLA-A0201-positive pancreatic cancer patient were subjected to next-generation sequencing, and bioinformatics analyses were performed to screen high-affinity and highly stable neoepitopes. The activation of cytotoxic T lymphocytes (CTLs) by dendritic cells (DCs) loaded with mutBCL2A111-20 neoepitope targeting a BCL2A1 mutant epitope was investigated, and the cytotoxicity of mutBCL2A111-20 neoepitope-specific CTLs to pancreatic cancer cells was evaluated. The mutBCL2A111-20 neoepitope was found to present a high immunogenicity and induce CTLs activation and proliferation, and these CTLs were cytotoxic to mutBCL2A111-20 neoepitope-loaded T2 cells and pancreatic cancer PANC-1-Neo and A2-BxPC-3-Neo cells that overexpressed mutBCL2A111-20 neoepitopes, appearing to be a targeting neoepitope specificity. In addition, high BCL2A1 expression correlated with a low 5-yr progression-free interval among pancreatic cancer patients. Our findings provide experimental supports to individualized T cell therapy targeting mutBCL2A111-20 neoepitopes, and provide an option of immunotherapy for pancreatic cancer.
摘要：
常规治疗对胰腺癌的疗效有限，免疫疗法是治疗这种高度致命的恶性肿瘤的新兴选择.新抗原对于提高肿瘤特异性免疫治疗的疗效至关重要。对人类白细胞抗原（HLA）-A0201阳性胰腺癌患者的癌症和外周血标本进行下一代测序，并进行生物信息学分析以筛选高亲和力和高度稳定的新表位。研究了靶向B细胞淋巴瘤2相关蛋白A1（BCL2A1）突变表位的mutBCL2A111-20新表位对细胞毒性T淋巴细胞（CTL）的激活，并评估了mutBCL2A111-20新表位特异性CTL对胰腺癌细胞的细胞毒性。发现mutBCL2A111-20新表位呈现高免疫原性并诱导CTL活化和增殖,并且对mutBCL2A111-20新表位负载的T2细胞和过表达mutBCL2A111-20新表位的胰腺癌PANC-1-Neo和A2-BxPC-3-Neo细胞具有细胞毒性，出现靶向新表位特异性。此外,在胰腺癌患者中,高BCL2A1表达与低5年无进展间隔(PFI)相关.我们的发现为靶向mutBCL2A111-20新表位的个性化T细胞治疗提供了实验支持，并为胰腺癌提供免疫治疗的选择。
