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^(+)...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.展开更多
基金supported by the National Natural Science Foundation of China(81930065,82173128,82102921,and 82003269)the Cancer Innovation Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004)+5 种基金the Swedish Research Council(VR-MH 2014-46602-117891-30)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-036)the Youth Teacher Cultivation Program of Sun Yat-sen UniversityGuangdong Provincial Clinical Medical Research Center for Malignant Tumors(84000-31660002)the China Postdoctoral Science Foundation(2023M744049)the Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center(CKS-SYSUCC-2023001)。
文摘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.
