Abstract
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.
基金项目
国家自然科学基金(81930065)
国家自然科学基金(82173128)
国家自然科学基金(82102921)
国家自然科学基金(82003269)
Cancer Innovation Research Program of Sun Yatsen University Cancer Center(CIRP-SYSUCC-0004)
Swedish Research Council(VR-MH 2014-46602-117891-30)
Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-I2M-5-036)
Youth Teacher Cultivation Program of Sun Yatsen University and Guangdong Provincial Clinical Medical Research Center for Mal(84000-31660002)
中国博士后科学基金(2023M744049)
Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yatsen University Cancer Center(CKS-SYSUCC-2023001)
NETL
NSTL
万方数据