肿瘤细胞治疗研究
英文原题：Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering.
Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering.
多发性骨髓瘤（MM）仍是一种无法治愈的血液系统肿瘤。
多发性骨髓瘤（MM）仍是一种无法治愈的血液系统肿瘤。新抗原特异性T细胞受体（TCR）工程化T（TCR-T）细胞疗法是一种潜在的替代治疗方法。特别是，来自第三方供体的TCR可能覆盖广泛的新抗原，而患有免疫疾病的患者中的TCR则有限。然而，治疗MM的疗效和可行性尚未得到全面评估。在本研究中，我们建立了一个系统，利用健康供体来源的外周血单个核细胞（PBMCs）来鉴定MM细胞上的免疫原性突变抗原及其相应的TCR。最初，研究了免疫基因组分析预测的35个候选肽的免疫反应。富集了肽反应性T淋巴细胞，随后通过单细胞TCR测序确定了TCR库。11个重建的TCR对4个肽显示出突变特异性反应。特别是，我们验证了源自COASY S55Y的HLA-A 24:02结合QYSPVQATF肽是MM细胞中天然加工的抗原表位，使其成为一个有前景的免疫靶点。相应的TCR特异性识别COASY S55Y + HLA-A 24:02 + MM细胞并增强了杀瘤活性。最后，过继性细胞转移TCR-T细胞在异种移植模型中显示出客观反应。我们首次提出利用肿瘤突变抗原特异性TCR基因来抑制MM。我们独特的策略将促进进一步鉴定新抗原特异性TCR。
Multiple myeloma (MM) remains an incurable hematological neoplasm. Neoantigen-specific T cell receptor (TCR)-engineered T (TCR-T) cell therapy is a potential alternative treatment. Particularly, TCRs derived from a third-party donor may cover broad ranges of neoantigens, whereas TCRs in patients suffering from immune disorders are limited. However, the efficacy and feasibility of treating MM have not been evaluated thoroughly. In this study, we established a system for identifying immunogenic mutant antigens on MM cells and their corresponding TCRs using healthy donor-derived peripheral blood mononuclear cells (PBMCs). Initially, the immune responses to 35 candidate peptides predicted by the immunogenomic analysis were investigated. Peptide-reactive T lymphocytes were enriched, and subsequently, TCR repertoires were determined by single-cell TCR sequencing. Eleven reconstituted TCRs showed mutation-specific responses against 4 peptides. Particularly, we verified the HLA-A 24:02-binding QYSPVQATF peptide derived from COASY S55Y as the naturally processed epitope across MM cells, making it a promising immune target. Corresponding TCRs specifically recognized COASY S55Y + HLA-A 24:02 + MM cells and augmented tumoricidal activity. Finally, adoptive cell transfer of TCR-T cells showed objective responses in the xenograft model. We initiatively proposed the utility of tumor mutated antigen-specific TCR genes to suppress MM. Our unique strategy will facilitate further identification of neoantigen-specific TCRs.
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