Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response
Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response
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确定的肿瘤抗原特异性 T 细胞增强个性化 TCR-T 细胞治疗和免疫治疗反应预测
DOI：
10.1038/s41422-022-00627-9
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发表时间：
2022-02-14
期刊：
影响因子：
44.1
通讯作者：
Zhou, Penghui
中科院分区：
文献类型：
--
作者：
He, Jingjing;Xiong, Xinxin;Zhou, Penghui
针对肿瘤特异性抗原（TSAs）的个体化免疫治疗可以在不损伤正常组织的情况下产生有效、安全的抗肿瘤免疫应答。虽然新抗原疫苗在临床试验中显示出治疗效果，但精确预测肿瘤突变的新抗原仍然具有挑战性。宿主抗肿瘤免疫应答选择并激活识别肿瘤抗原的T细胞。因此，用来自患者中这些天然存在的肿瘤抗原特异性T（Tas）细胞的T细胞受体（TCR）工程化的T细胞将靶向他/她的肿瘤中的个人TSAs。为了建立这种个性化的TCR-T细胞疗法，我们通过单细胞mRNA测序（scRNA-seq）、TCR测序（TCR-seq）和体外新抗原刺激来全面表征肿瘤及其邻近组织中的T细胞。与组织间循环的旁观者T细胞相比，Tas细胞的特征在于肿瘤富集、肿瘤特异性克隆扩增和新抗原特异性。我们发现CXCL 13是CD 4（+）和CD 8（+）Tas细胞的独特标志物。重要的是，表达来自Tas细胞的TCR的TCR-T细胞对自体患者来源的异种移植（PDX）肿瘤显示出显著的治疗效果。通过CXCL 13表达测量的肿瘤内Tas细胞水平精确预测了对免疫检查点阻断的应答，表明Tas细胞在抗肿瘤免疫中的关键作用。我们进一步鉴定了CD 200和ENTPD 1分别作为CD 4（+）和CD 8（+）Tas细胞的表面标志物，这使得能够通过荧光激活细胞分选仪（FACS）分选从肿瘤中分离Tas细胞。总的来说，我们的研究结果表明，用Tas TCR工程化的TCR-T细胞是个性化免疫治疗的有希望的试剂，并且肿瘤内Tas细胞水平决定了对免疫治疗的反应。
Personalized immunotherapy targeting tumor-specific antigens (TSAs) could generate efficient and safe antitumor immune response without damaging normal tissues. Although neoantigen vaccines have shown therapeutic effect in clinic trials, precise prediction of neoantigens from tumor mutations is still challenging. The host antitumor immune response selects and activates T cells recognizing tumor antigens. Hence, T cells engineered with T-cell receptors (TCRs) from these naturally occurring tumor antigen-specific T (Tas) cells in a patient will target personal TSAs in his/her tumor. To establish such a personalized TCR-T cell therapy, we comprehensively characterized T cells in tumor and its adjacent tissues by single-cell mRNA sequencing (scRNA-seq), TCR sequencing (TCR-seq) and in vitro neoantigen stimulation. Compared to bystander T cells circulating among tissues, Tas cells were characterized by tumor enrichment, tumor-specific clonal expansion and neoantigen specificity. We found that CXCL13 is a unique marker for both CD4(+) and CD8(+) Tas cells. Importantly, TCR-T cells expressing TCRs from Tas cells showed significant therapeutic effects on autologous patient-derived xenograft (PDX) tumors. Intratumoral Tas cell levels measured by CXCL13 expression precisely predicted the response to immune checkpoint blockade, indicating a critical role of Tas cells in the antitumor immunity. We further identified CD200 and ENTPD1 as surface markers for CD4(+) and CD8(+) Tas cells respectively, which enabled the isolation of Tas cells from tumor by Fluorescence Activating Cell Sorter (FACS) sorting. Overall, our results suggest that TCR-T cells engineered with Tas TCRs are a promising agent for personalized immunotherapy, and intratumoral Tas cell levels determine the response to immunotherapy.