Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, China.
Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm S-171 21, Sweden; Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
Sci Bull (Beijing). 2024 Mar 30;69(6):803-822. doi: 10.1016/j.scib.2024.01.025. Epub 2024 Jan 19.
Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8 T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8 T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8 T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8 T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8 T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8 T cell infiltration and improve ICI efficacy.
患有高肿瘤突变负担（TMB）水平的患者并不一致地对免疫检查点抑制剂（ICI）产生反应，这可能是因为高 TMB 水平不一定导致 CD8 T 细胞的充分浸润。使用来自 30 种癌症类型的 9311 个肿瘤样本的批量核糖核酸测序（RNA-seq）数据，我们开发了一种称为与 TMB 相关的免疫浸润调节剂（MOTIF）的新型工具，该工具包含可以确定由特定 TMB 水平引发的 CD8 T 细胞浸润程度的基因。我们证实 MOTIF 可以准确反映癌症免疫循环的完整性和缺陷。通过分析来自 32 种实体瘤的 84 个人类单细胞 RNA-seq 数据集，我们揭示了 MOTIF 可以深入了解各种细胞类型在调节 CD8 T 细胞浸润方面的不同作用。使用来自 13 个接受 ICI 治疗的队列的预处理 RNA-seq 数据，我们验证了 MOTIF 在预测 CD8 T 细胞浸润和 ICI 疗效方面的用途。在 MOTIF 的组成部分中，我们确定 EMC3 是 CD8 T 细胞浸润的负调节剂，通过体内研究进行了验证。此外，MOTIF 为程序性死亡 1 阻断与某些免疫刺激性药物的潜在联合使用提供了指导，以促进 CD8 T 细胞浸润并提高 ICI 疗效。
Int Immunopharmacol. 2020-12
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