结直肠癌是世界高发和高致死率的恶性肿瘤。靶向新抗原的免疫治疗已被证实可以诱导癌症患者肿瘤持续消退,但这些特异性新抗原,仅适用于个体精准治疗。随着大量的高频肿瘤基因突变被发现,这些与突变相关的高频新抗原可覆盖更多人群,具有...结直肠癌是世界高发和高致死率的恶性肿瘤。靶向新抗原的免疫治疗已被证实可以诱导癌症患者肿瘤持续消退,但这些特异性新抗原,仅适用于个体精准治疗。随着大量的高频肿瘤基因突变被发现,这些与突变相关的高频新抗原可覆盖更多人群,具有较强的临床意义。然而目前结直肠癌中是否也存在高频新抗原仍不清楚。本研究利用来源于321个结直肠癌患者的体细胞突变数据库,联合1种标准过滤和7种预测算法,筛选并获得了25个基于中国人高频分型HLA-A^*1101限制性的高频新抗原,它们均具有高亲和力(IC50<50 nmol/L)和高呈递分值(>0.90);其中,除了阳性对照多肽KRAS_G12V8-16外,11个高频新抗原能够在体外诱导细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)分泌γ干扰素(interferon gamma,IFN-γ),证实具有免疫原性。选取免疫原性最强的新抗原C1orf170_S418G413-421及阳性对照多肽KRAS_G12V8-16体外刺激T细胞,利用流式细胞分选及单细胞转录组测序技术,获得其特异性CTL的免疫组库信息,所构建的TCR-T(T-cell receptor engineered T cell)能够识别新抗原并分泌细胞因子。以上结果表明,本研究开发了一种利用体细胞数据库预测并体外筛选验证具有免疫原性高频新抗原的方法,为结直肠癌及其他癌种的多肽、DC(dendritic cells)疫苗、TCR-like抗体、TCR-T等免疫治疗提供了重要的多肽靶点和TCR信息,具有实际的临床应用价值。展开更多
To adapt to changing environments, plants have evolved elaborate regulatory mechanisms balancing their growth with stress responses. It is currently unclear whether and how the tryptophan (Trp), the growth-related hor...To adapt to changing environments, plants have evolved elaborate regulatory mechanisms balancing their growth with stress responses. It is currently unclear whether and how the tryptophan (Trp), the growth-related hormone auxin, and the stress hormone abscisic acid (ABA) are coordinated in this trade-off. Here, we show that tryptophan synthase β subunit 1 (TSB1) is involved in the coordination of Trp and ABA, thereby affecting plant growth and abiotic stress responses. Plants experiencing high salinity or drought display reduced TSB1 expression, resulting in decreased Trp and auxin accumulation and thus reduced growth. In comparison with the wild type, amiR-TSB1 lines and TSB1 mutants exhibited repressed growth under non-stress conditions but had enhanced ABA accumulation and stress tolerance when subjected to salt or drought stress. Furthermore, we found that TSB1 interacts with and inhibits β-glucosidase 1 (BG1), which hydrolyses glucose-conjugated ABA into active ABA. Mutation of BG1 in the amiR-TSB1 lines compromised their increased ABA accumulation and enhanced stress tolerance. Moreover, stress-induced H2O2 disrupted the interaction between TSB1 and BG1 by sulfenylating cysteine-308 of TSB1, relieving the TSB1-mediated inhibition of BG1 activity. Taken together, we revealed that TSB1 serves as a key coordinator of plant growth and stress responses by balancing Trp and ABA homeostasis.展开更多
文摘结直肠癌是世界高发和高致死率的恶性肿瘤。靶向新抗原的免疫治疗已被证实可以诱导癌症患者肿瘤持续消退,但这些特异性新抗原,仅适用于个体精准治疗。随着大量的高频肿瘤基因突变被发现,这些与突变相关的高频新抗原可覆盖更多人群,具有较强的临床意义。然而目前结直肠癌中是否也存在高频新抗原仍不清楚。本研究利用来源于321个结直肠癌患者的体细胞突变数据库,联合1种标准过滤和7种预测算法,筛选并获得了25个基于中国人高频分型HLA-A^*1101限制性的高频新抗原,它们均具有高亲和力(IC50<50 nmol/L)和高呈递分值(>0.90);其中,除了阳性对照多肽KRAS_G12V8-16外,11个高频新抗原能够在体外诱导细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)分泌γ干扰素(interferon gamma,IFN-γ),证实具有免疫原性。选取免疫原性最强的新抗原C1orf170_S418G413-421及阳性对照多肽KRAS_G12V8-16体外刺激T细胞,利用流式细胞分选及单细胞转录组测序技术,获得其特异性CTL的免疫组库信息,所构建的TCR-T(T-cell receptor engineered T cell)能够识别新抗原并分泌细胞因子。以上结果表明,本研究开发了一种利用体细胞数据库预测并体外筛选验证具有免疫原性高频新抗原的方法,为结直肠癌及其他癌种的多肽、DC(dendritic cells)疫苗、TCR-like抗体、TCR-T等免疫治疗提供了重要的多肽靶点和TCR信息,具有实际的临床应用价值。
基金supported by National Natural Science Foundation of China(#no.31830007,#no.32000150.and#no.31670251)the Natural Science Foundation of Henan Province(#no.222300420401)。
文摘To adapt to changing environments, plants have evolved elaborate regulatory mechanisms balancing their growth with stress responses. It is currently unclear whether and how the tryptophan (Trp), the growth-related hormone auxin, and the stress hormone abscisic acid (ABA) are coordinated in this trade-off. Here, we show that tryptophan synthase β subunit 1 (TSB1) is involved in the coordination of Trp and ABA, thereby affecting plant growth and abiotic stress responses. Plants experiencing high salinity or drought display reduced TSB1 expression, resulting in decreased Trp and auxin accumulation and thus reduced growth. In comparison with the wild type, amiR-TSB1 lines and TSB1 mutants exhibited repressed growth under non-stress conditions but had enhanced ABA accumulation and stress tolerance when subjected to salt or drought stress. Furthermore, we found that TSB1 interacts with and inhibits β-glucosidase 1 (BG1), which hydrolyses glucose-conjugated ABA into active ABA. Mutation of BG1 in the amiR-TSB1 lines compromised their increased ABA accumulation and enhanced stress tolerance. Moreover, stress-induced H2O2 disrupted the interaction between TSB1 and BG1 by sulfenylating cysteine-308 of TSB1, relieving the TSB1-mediated inhibition of BG1 activity. Taken together, we revealed that TSB1 serves as a key coordinator of plant growth and stress responses by balancing Trp and ABA homeostasis.
