肿瘤细胞治疗研究
英文原题：Dissection of the T cell infiltrate in mouse pancreatic tumors reveals an extensive and diverse tumor-reactive T cell repertoire.
Dissection of the T cell infiltrate in mouse pancreatic tumors reveals an extensive and diverse tumor-reactive T cell repertoire.
尽管胰腺癌通常对免疫检查点阻断无效，但近期对人类肿瘤样本中肿瘤浸润性T细胞的研究表明，存在体内扩增的肿瘤反应性T细胞受体（TCR）克隆型。
尽管胰腺癌通常对免疫检查点阻断无效，但近期对人类肿瘤样本中肿瘤浸润性T细胞的研究表明，存在体内扩增的、肿瘤反应性T细胞受体（TCR）克隆型。在此，我们通过将单细胞转录组学与功能性TCR表征相结合，探索了小鼠胰腺癌模型中的T细胞库。这揭示了肿瘤反应性TCR克隆型的显著多样性。其中一些仅对自体肿瘤具有反应性，而大多数TCR对来自不同组织来源的同系肿瘤细胞均有反应。免疫肽组分析揭示了三个T细胞表位，反映了在人类癌症中也发现的不同肿瘤抗原类别：一个由突变组编码的新抗原、一个由异位表达的内源性逆转录病毒前病毒编码的表位，以及一个来源于细胞应激诱导的自身抗原的表位。这些发现强调了揭示天然肿瘤反应性TCR库的抗原特异性对于评估其在个性化免疫治疗中的治疗潜力和安全性的重要性。
Although pancreatic cancer is generally refractory to immune checkpoint blockade, recent studies of tumor-infiltrating T cells in human tumor samples demonstrated the presence of in vivo expanded, tumor-reactive T cell receptor (TCR) clonotypes. Here, we explored the T cell repertoire in a murine pancreatic cancer model by combining single-cell transcriptomics with functional TCR characterization. This uncovered a substantial diversity of tumor-reactive TCR clonotypes. Whereas some of these were exclusively reactive against the autologous tumor, most TCRs reacted against syngeneic tumor cells of diverse tissue origin. Immunopeptidome analyses revealed three T cell epitopes reflecting distinct tumor antigen classes also found in human cancers: a mutanome-encoded neoantigen, an epitope encoded by an ectopically expressed endogenous retroviral provirus, and an epitope derived from a cell stress-induced autoantigen. These findings underline the importance of uncovering the antigen specificity of the natural tumor-reactive TCR repertoire to assess its therapeutic potential and safety with regard to personalized immunotherapy.
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