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

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

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Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune check-point inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltra-tion 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 infil-tration(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 compo-nents 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.

Tumor mutational burdenImmunotherapyCancer-immunity cycleTreatment efficacy predictionCD8+T cell infiltrationCombination therapy

Zheng-Yu Qian、Yi-Qian Pan、Xue-Xin Li、Yan-Xing Chen、Hao-Xiang Wu、Ze-Xian Liu、Martin Kosar、Jiri Bartek、Zi-Xian Wang、Rui-Hua Xu

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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

Bioinformatics Platform,Sun Yat-sen University Cancer Center,Guangzhou 510060,China

Laboratory of Artificial Intelligence and Data Science,Sun Yat-se

Zhejiang University-University of Edinburgh Institute,Zhejiang University School of Medicine,Haining 314400,China

Edinburgh Medical School,Biomedical Sciences,College of Medicine and Veterinary Medicine,The University of Edinburgh,Edinburgh EH1 1LT,UK

Danish Cancer Society Research Center,Copenhagen DK-2100,Denmark

Laboratory of Artificial Intelligence and Data Science,Sun Yat-sen University Cancer Center,Guangzhou 510060,China

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国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Cancer Innovation Research Program of Sun Yatsen University Cancer CenterSwedish Research CouncilChinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical SciencesYouth Teacher Cultivation Program of Sun Yatsen University and Guangdong Provincial Clinical Medical Research Center for Mal中国博士后科学基金Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yatsen University Cancer Center

81930065821731288210292182003269CIRP-SYSUCC-0004VR-MH 2014-46602-117891-302019-I2M-5-03684000-316600022023M744049CKS-SYSUCC-2023001

2024

10.1016/j.scib.2024.01.025

科学通报(英文版)
中国科学院

科学通报(英文版)

CSTPCD
ISSN：1001-6538
年,卷(期)：2024.69(6)
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