Department of Hematology, Peking University First Hospital, Beijing, China.
Front Immunol. 2022 Jul 28;13:927804. doi: 10.3389/fimmu.2022.927804. eCollection 2022.
Multiple myeloma (MM) is a malignant plasma cell disorder affecting mainly the elderly population. Revolutionary progress in immunotherapy has been made recently, including monoclonal antibodies and chimeric antigen receptor T cell (CAR-T) therapies; however, the high relapse rate remains problematic. Therefore, combination therapies against different targets would be a reasonable strategy. In this study, we present a new X-chromosome encoded testis-cancer antigen (CTA) AKAP4 as a potential target for MM. AKAP4 is expressed in MM cell lines and MM primary malignant plasma cells. HLA-A0201-restricted cytotoxic T lymphocytes (CTLs) induced by dendritic cells (DCs) transduced with an adenovirus vector encoding the full-length gene were demonstrated to lyse AKAP4 myeloma cells. Seven of the 12 candidate epitopes predicated by the BIMAS and SYFPEITH algorithms were able to bind HLA-A0201 in the T2 binding assay, of which only two peptides were able to induce CTL cytotoxicity in the co-culture of peptide-loaded human mature dendritic cells and the autologous peripheral blood mononuclear cells (PBMCs) from the same HLA-A0201 donor. The AKAP4 630-638 VLMLIQKLL was identified as the strongest CTL epitope by the human IFN-γ ELISPOT assay. Finally, the VLMLIQKLL-specific CTLs can lyse the HLA-A0201AKAP4 myeloma cell line U266 , and inhibit tumor growth in the mice bearing U266 tumors . These results suggest that the VLMLIQKLL epitope could be used to develop cancer vaccine or T-cell receptor transgenic T cells (TCR-T) to kill myeloma cells.
多发性骨髓瘤（MM）是一种主要影响老年人群的恶性浆细胞疾病。最近，免疫疗法取得了革命性进展，包括单克隆抗体和嵌合抗原受体 T 细胞（CAR-T）疗法；然而，高复发率仍然是一个问题。因此，针对不同靶点的联合治疗将是一种合理的策略。在这项研究中，我们提出了一种新的 X 染色体编码的睾丸癌抗原（CTA）AKAP4 作为 MM 的潜在靶点。AKAP4 在 MM 细胞系和 MM 原发性恶性浆细胞中表达。用腺病毒载体转导的树突状细胞（DC）诱导的 HLA-A0201 限制性细胞毒性 T 淋巴细胞（CTL）被证明可以溶解 AKAP4 骨髓瘤细胞。通过 BIMAS 和 SYFPEITH 算法预测的 12 个候选表位中有 7 个能够在 T2 结合试验中与 HLA-A0201 结合，其中只有 2 个肽能够在负载肽的人成熟树突状细胞和相同 HLA-A0201 供体的自体外周血单核细胞（PBMC）共培养物中诱导 CTL 细胞毒性。通过人 IFN-γ ELISPOT 测定鉴定 AKAP4 630-638 VLMLIQKLL 为最强的 CTL 表位。最后，VLMLIQKLL 特异性 CTLs 可以溶解 HLA-A0201AKAP4 骨髓瘤细胞系 U266，并抑制携带 U266 肿瘤的小鼠中的肿瘤生长。这些结果表明，VLMLIQKLL 表位可用于开发癌症疫苗或 T 细胞受体转基因 T 细胞（TCR-T）以杀死骨髓瘤细胞。
