患者的T细胞可在体外改造，使其表达具有定义的新型抗原特异性的T细胞受体（TCR），成为一种方便的癌症治疗方式。在大多数情况下，CD8+ T细胞表达限制于主要组织相容性（MHC）I的TCR，而CD4+ T细胞的开发则滞后于表达限制于MHC II的TCR。关键是选择目标抗原，无论表位是否高效处理且与MHC分子具有高亲和力。转化生长因子β受体2(TGFβR2(-1))基因的突变在微卫星不稳定的结肠和胃癌中经常出现，因此是一种真正特异性的肿瘤抗原，多位患者检测到它。以人类MHC II分子HLA-DRA/DRB1*0401(HLA-DR4)限制的多样人类TCR库ABabDR4小鼠，受TGFβR2(-1)肽段免疫，然后从响应的CD4+ T细胞中分离出TGFβR2(-1)-特异性TCR。表达TGFβR2(-1)-特异性TCR的人类CD4+ T细胞通过共培养和其他功能性检验来评估它们的效力和安全性。我们证明了TGFβR2(-1)新抗原是有免疫原性的，在ABabDR4小鼠中引发CD4+ T细胞的反应。当表达于人类CD4+ T细胞中时，HLA-DR4限制的TGFβR2(-1)-特异性TCR在低TGFβR2(-1)肽段的数量下诱导IFNy表达。TGFβR2(-1)-特异性TCR识别HLA-DR4+淋巴母细胞瘤细胞，这些细胞内源性处理并呈现新抗原，并识别自然表达TGFβR2(-1)突变的结肠癌细胞系SW48和HCT116。没有观察到MHC II的非同种反应性或对具有相似TCR识别模体的肽段的交叉反应性，表明TCR的安全性。数据表明，HLA-DR4限制的针对TGFβR2(-1)复发新抗原的TCR可成为大量癌症患者的采用性T细胞治疗有价值的候选物。©作者(或其雇主)2023。根据CC BY-NC的规定进行重复使用。不商业用途。由BMJ出版。

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.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.