肿瘤细胞治疗研究
英文原题：Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy.
Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy.
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数据表明，针对 TGFβR2(-1) 复发性新抗原的 HLA-DR4 限制性 TCR 可作为相当数量癌症患者过继性 T 细胞治疗的有价值候选方案。
过继转移患者T细胞，经工程化表达具有明确新抗原特异性的T细胞受体（TCR），是一种便捷的癌症治疗形式。在大多数情况下，主要组织相容性复合体（MHC）I类限制性TCR表达于CD8+ T细胞中，而工程化表达MHC II类限制性TCR的CD4+ T细胞的开发则相对滞后。关键在于靶抗原的选择，即表位是否能被有效加工并以高亲和力与MHC分子结合。转化生长因子β受体2（TGFβR2(-1)）基因中的突变因微卫星序列内一个腺嘌呤的缺失（-1）而产生移码肽。这种体细胞突变在微卫星不稳定性结直肠癌和胃癌中反复出现，因此是一种在许多患者中检测到的真正肿瘤特异性抗原。
ABabDR4 小鼠表达受人类 MHC II 类分子 HLA-DRA/DRB1*0401（HLA-DR4）限制的多样化人类 TCR 库，用 TGFβR2(-1) 肽免疫这些小鼠，并从应答的 CD4+ T 细胞中分离出 TGFβR2(-1) 特异性 TCR。将 TGFβR2(-1) 特异性 TCR 表达于人类 CD4+ T 细胞中，并通过共培养及其他功能试验评估其效力和安全性特征。
我们证明 TGFβR2(-1) 新抗原具有免疫原性，并在 ABabDR4 小鼠中诱导了 CD4 + T 细胞应答。当在人 CD4 + T 细胞中表达时，HLA-DR4 限制性 TGFβR2(-1) 特异性 TCR 在低 TGFβR2(-1) 肽量下诱导 IFNy 表达。TGFβR2(-1) 特异性 TCR 识别 HLA-DR4 + 淋巴母细胞样细胞，这些细胞内源性加工并呈递该新抗原，以及天然表达 TGFβR2(-1) 突变的结直肠癌细胞系 SW48 和 HCT116。未观察到 MHC II 同种反应性或对具有相似 TCR 识别基序的肽的交叉反应性，表明这些 TCR 是安全的。
Adoptive transfer of patient's T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8 + T cells and the development of CD4 + T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients.
ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLA-DRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4 + T cells. The TGFβR2(-1)-specific TCRs were expressed in human CD4 + T cells and their potency and safety profile were assessed by co-cultures and other functional assays.
We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4 + T cell responses in ABabDR4 mice. When expressed in human CD4 + T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4 + lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs.
The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer.
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