Qu Chuang, Gao Shuhui, Shao Hongwei, Zhang Wenfeng, Bo Huabben, Lu Xin, Chen Tianjiao, Kou Jing, Wang Yue, Chen Gui Si, Huang Shulin, Shen Han
Guangdong Province Key Laboratory of Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China.
School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China.
Oncol Lett. 2018 Apr;15(4):6050-6056. doi: 10.3892/ol.2018.8085. Epub 2018 Feb 16.
Cluster of differentiation (CD)147 is highly expressed in drug-resistant tumor cell lines and is involved in the formation of tumor drug resistance. Therefore, immunotherapy utilizing CD147 epitope peptides is a promising approach for the elimination of drug-resistant tumor cells. However, like most tumor-associated antigens (TAAs), CD147 belongs to the autoantigen category, and T cells that recognize high affinity, immunodominant epitopes from autoantigens are deleted though thymic negative selection. Furthermore, wild-type autoantigen peptides cannot effectively activate and expand T lymphocytes with lower affinity T cell receptors . However, mutations of TAA peptides have been demonstrated to increase the affinity of major histocompatibility complex molecules and their binding to T cell receptor molecules, leading to activation of T lymphocytes . In the present study, a high-affinity point mutation peptide, CD147L2, was predicted by the human leukocyte antigen (HLA) binding prediction algorithm and its affinity was testified using a T2 binding assay. In addition, when peptide-specific cytotoxic T lymphocytes (CTLs) were stimulated with dendritic cells loaded with the CD147L2 peptide under HLA-A02:01 restriction, interferon-γ release and cytotoxicity assays showed that peptide-specific CTLs effectively cross-recognized and lysed T2 target cells loaded either with the wild-type (CD147) or mutated peptide (CD147L2). Moreover, the CD147L2 peptide-specific CTLs exerted strong cytotoxic activity against drug-resistant MCF-7/Adr cells, which express a high level of CD147 and are HLA-A02:01-positive, but not against normal MCF-7 cells. Thus, this suggests that the wild-type peptide (CD147) is naturally presented on HLA-A02:01 of CD147-expressing MCF-7/Adr cells and is cross-recognized by CTLs. In conclusion, an HLA-A02:01-restricted CD147-point mutant epitope peptide was identified that induces CTLs to efficiently lyse drug-resistant MCF-7 cells that highly express CD147. Therefore, this immunotherapeutic approach should be explored as a potential treatment for drug-resistant tumors.
分化簇（CD）147在耐药肿瘤细胞系中高表达，并参与肿瘤耐药的形成。因此，利用CD147表位肽进行免疫治疗是消除耐药肿瘤细胞的一种有前景的方法。然而，与大多数肿瘤相关抗原（TAA）一样，CD147属于自身抗原类别，识别来自自身抗原的高亲和力、免疫显性表位的T细胞会通过胸腺阴性选择被清除。此外，野生型自身抗原肽不能有效激活和扩增具有较低亲和力T细胞受体的T淋巴细胞。然而，已证明TAA肽的突变可增加主要组织相容性复合体分子的亲和力及其与T细胞受体分子的结合，从而导致T淋巴细胞的激活。在本研究中，通过人类白细胞抗原（HLA）结合预测算法预测了一种高亲和力点突变肽CD147L2，并使用T2结合试验证实了其亲和力。此外，当在HLA-A02:01限制下用负载CD147L2肽的树突状细胞刺激肽特异性细胞毒性T淋巴细胞（CTL）时，干扰素-γ释放和细胞毒性试验表明，肽特异性CTL有效地交叉识别并裂解负载野生型（CD147）或突变肽（CD147L2）的T2靶细胞。此外，CD147L2肽特异性CTL对耐药MCF-7/Adr细胞具有强大的细胞毒性活性，这些细胞表达高水平的CD147且HLA-A02:01呈阳性，但对正常MCF-7细胞无细胞毒性活性。因此，这表明野生型肽（CD147）天然呈递在表达CD147的MCF-7/Adr细胞的HLA-A02:01上，并被CTL交叉识别。总之，鉴定出一种HLA-A02:01限制的CD147点突变表位肽，其可诱导CTL有效裂解高表达CD147的耐药MCF-7细胞。因此，应探索这种免疫治疗方法作为耐药肿瘤的潜在治疗手段。
