中山大学Rui-Hua Xu等研究人员合作发现，TMB相关免疫浸润调节因子（MOTIF）可预测免疫疗法反应并指导联合疗法。这一研究成果于2024年1月19日在线发表在国际学术期刊《科学通报》上。

利用来自30种癌症类型9311份肿瘤样本的大量核糖核酸测序（RNA-seq）数据，研究人员开发出了一种名为肿瘤突变负荷（TMB）相关免疫浸润调节因子（MOTIF）的新型工具，该工具由一些基因组成，这些基因可以确定特 TMB水平所引起的CD8⁺ T细胞浸润程度。研究人员证实，MOTIF能准确反映癌症免疫周期的完整性和缺陷。通过分析来自32种实体瘤的84个人类单细胞RNA-seq数据集，研究人员发现MOTIF能深入揭示各种细胞类型在调节CD8⁺ T细胞浸润中的不同作用。

利用13个免疫检查点抑制剂（ICI）治疗队列的预处理RNA-seq数据，研究人员验证了MOTIF在预测CD8⁺ T细胞浸润和ICI疗效方面的应用。在MOTIF的成分中，研究人员发现EMC3是CD8⁺ T细胞浸润的负调控因子，这一点通过体内研究得到了验证。此外，MOTIF还为程序性死亡1阻断与某些免疫刺激药物的潜在组合提供了指导，以便促进CD8⁺ T细胞浸润并提高ICI疗效。

据了解，TMB水平高的患者对ICI的反应并不一致，这可能是因为TMB水平高并不一定会导致CD8⁺ T细胞的充分浸润。

附：英文原文

Title: Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy

Author: anonymous

Issue&Volume: 2024/01/19

Abstract: 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.

DOI: 10.1016/j.scib.2024.01.025

Source: https://www.sciencedirect.com/science/article/pii/S2095927324000434