识别在新鲜人类肺癌中新抗原反应性T细胞表型特征

SUMMARY 摘要

A common theme across multiple successful immunotherapies for cancer is the recognition of tumor-specific mutations (neoantigens) by T cells. The rapid discovery of such antigen responses could lead to improved therapies through the adoptive transfer of T cells engineered to express neoantigen-reactive T cell receptors (TCRs). Here, through CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and TCR-seq of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TILs), we develop a neoantigen-reactive T cell signature based on clonotype frequency and CD39 protein and CXCL13mRNA expression. Screening of TCRs selected by the signature allows us to identify neoantigen-reactive TCRs with a success rate of 45% for CD8+ and 66% for CD4+ T cells. Because of the small number of samples analyzed (4 patients), generalizability remains to be tested. However, this approach can enable the quick identification of neoantigen-reactive TCRs and expedite the engineering of personalized neoantigen-reactive T cells for therapy.

多种成功的癌症免疫疗法的共同主题是T细胞识别肿瘤特异性突变（新抗原）。这种快速发现的抗原反应通过被设计为表达新抗原反应性T细胞受体（TCR）的获得转移性T细胞来改善治疗。此处，通过对非小细胞肺癌（NSCLC）肿瘤浸润淋巴细胞（TIL）的CITE-seq（通过测序对转录组和表位进行细胞索引）和TCR-seq，我们基于克隆型频率、CD39蛋白和CXCL13mRNA表达开发了新抗原反应性T细胞标记。通过对特征选择的TCR进行筛查，我们可以识别新抗原反应性TCR，CD8+和CD4+T细胞筛查的成功率分别为45%和66%。由于分析的样本数量较少（4名患者），研究的普遍性仍有待检验。然而，这种方法可以快速识别新抗原反应性TCR，并加快个性化新抗原反应性T细胞的工程化以进行治疗。