Targeting B-cell malignancies through human B-cell receptor specific CD4+ T cells
Targeting B-cell malignancies through human B-cell receptor specific CD4+ T cells
复制标题
通过人类 B 细胞受体特异性 CD4 T 细胞靶向 B 细胞恶性肿瘤
DOI：
10.1080/2162402x.2016.1232220
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发表时间：
2016
期刊：
影响因子：
7.2
通讯作者：
L. W. Kwak
中科院分区：
文献类型：
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作者：
J. Weng;F. E. Baio;K. E. Moriarty;H. Torikai;H. Wang;Z. Liu;S. N. Maiti;D. Gwak;M. S. Popescu;S. C. Cha;L. J. Cooper;S. S. Neelapu;L. W. Kwak
克隆性B细胞肿瘤表达的B细胞受体(BCR)是一种肿瘤特异性抗原(独特型)。然而，人类BCR中激发保护性免疫的T细胞表位仍然缺乏详细的表征。在这项研究中，我们从BCR重链可变区和轻链可变区序列中鉴定了17个BCR多肽特异性的CD4+T细胞表位。详细分析发现，这些CD_4~+T细胞表位刺激正常供者和患者的Th1CD_4~+T细胞通过分泌干扰素γ直接识别自体肿瘤，表明这些表位是由肿瘤细胞加工和呈递的。一个BCR多肽特异性的CD4+T细胞系也具有细胞毒性，并通过穿孔素途径裂解自体肿瘤细胞。序列分析表明，10个表位由多个原发患者肿瘤共享，16个表位具有与一个以上HLADRB1等位基因结合的能力。由共享表位刺激的T细胞识别在多个HLADRB1等位基因上表达相同序列的原发肿瘤。总之，我们确定了17个BCR来源的CD4+T细胞表位，它们具有混杂的HLADRB1结合亲和力，高达36%的患者共享这些表位，这表明了一种策略，以克服针对独特型的个体化治疗药物的需求。
The B-cell receptor (BCR) expressed by a clonal B cell tumor is a tumor specific antigen (idiotype). However, the T-cell epitopes within human BCRs which stimulate protective immunity still lack detailed characterization. In this study, we identified 17 BCR peptide-specific CD4+T-cell epitopes derived from BCR heavy and light chain variable region sequences. Detailed analysis revealed these CD4+T-cell epitopes stimulated normal donors' and patients' Th1 CD4+T cells to directly recognize the autologous tumors by secretion of IFNγ, indicating the epitopes are processed and presented by tumor cells. One BCR peptide-specific CD4+T cell line was also cytotoxic and lysed autologous tumor cells through the perforin pathway. Sequence analysis of the epitopes revealed that 10 were shared by multiple primary patients' tumors, and 16 had the capacity to bind to more than one HLA DRB1 allele. T cells stimulated by shared epitopes recognized primary tumors expressing the same sequences on multiple HLA DRB1 alleles. In conclusion, we identified 17 BCR-derived CD4+T-cell epitopes with promiscuous HLA DRB1 binding affinity that are shared by up to 36% of patients, suggesting a strategy to overcome the requirement for individual preparation of therapeutic agents targeting idiotype.