Unraveling the role of M1 macrophage and CXCL9 in predicting immune checkpoint inhibitor efficacy through multicohort analysis and single‐cell RNA sequencing
Yunfang Yu,
Haizhu Chen,
Wenhao Ouyang,
Jin Zeng,
Hong Huang,
Luhui Mao,
Xueyuan Jia,
Taihua Guan,
Zehua Wang,
Ruichong Lin,
Zhenjun Huang,
Hanqi Yin,
Herui Yao,
Kang Zhang
Affiliations
Yunfang Yu
Faculty of Medicine Macau University of Science and Technology Macao P. R. China
Haizhu Chen
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Department of Medical Oncology Breast Tumor Centre Phase I Clinical Trial Centre Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou P. R. China
Wenhao Ouyang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Department of Medical Oncology Breast Tumor Centre Phase I Clinical Trial Centre Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou P. R. China
Jin Zeng
Faculty of Sustainable Development Macau University of Science and Technology Macau P. R. China
Hong Huang
School of Medicine Guilin Medical University Guilin P. R. China
Luhui Mao
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Department of Medical Oncology Breast Tumor Centre Phase I Clinical Trial Centre Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou P. R. China
Xueyuan Jia
Faculty of Medicine Macau University of Science and Technology Macao P. R. China
Taihua Guan
Guangzhou National Laboratory Guangzhou P. R. China
Zehua Wang
Division of Science and Technology Beijing Normal University‐Hong Kong Baptist University United International College Zhuhai P. R. China
Ruichong Lin
Faculty of Innovation Engineering Macau University of Science and Technology Macao P. R. China
Zhenjun Huang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Department of Medical Oncology Breast Tumor Centre Phase I Clinical Trial Centre Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou P. R. China
Hanqi Yin
South China Institute of Biomedine Guangzhou China
Herui Yao
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Department of Medical Oncology Breast Tumor Centre Phase I Clinical Trial Centre Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou P. R. China
Kang Zhang
Faculty of Medicine Macau University of Science and Technology Macao P. R. China
Abstract The exact function of M1 macrophages and CXCL9 in forecasting the effectiveness of immune checkpoint inhibitors (ICIs) is still not thoroughly investigated. We investigated the potential of M1 macrophage and C‐X‐C Motif Chemokine Ligand 9 (CXCL9) as predictive markers for ICI efficacy, employing a comprehensive approach integrating multicohort analysis and single‐cell RNA sequencing. A significant correlation between high M1 macrophage and improved overall survival (OS) and objective response rate (ORR) was found. M1 macrophage expression was most pronounced in the immune‐inflamed phenotype, aligning with increased expression of immune checkpoints. Furthermore, CXCL9 was identified as a key marker gene that positively correlated with M1 macrophage and response to ICIs, while also exhibiting associations with immune‐related pathways and immune cell infiltration. Additionally, through exploring RNA epigenetic modifications, we identified Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3G (APOBEC3G) as linked to ICI response, with high expression correlating with improved OS and immune‐related pathways. Moreover, a novel model based on M1 macrophage, CXCL9, and APOBEC3G‐related genes was developed using multi‐level attention graph neural network, which showed promising predictive ability for ORR. This study illuminates the pivotal contributions of M1 macrophages and CXCL9 in shaping an immune‐active microenvironment, correlating with enhanced ICI efficacy. The combination of M1 macrophage, CXCL9, and APOBEC3G provides a novel model for predicting clinical outcomes of ICI therapy, facilitating personalized immunotherapy.
