Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception.

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作者:Zhu Bo, Chen Pingjun, Aminu Muhammad, Li Jian-Rong, Fujimoto Junya, Tian Yanhua, Hong Lingzhi, Chen Hong, Hu Xin, Li Chenyang, Vokes Natalie, Moreira Andre L, Gibbons Don L, Solis Soto Luisa M, Parra Cuentas Edwin Roger, Shi Ou, Diao Songhui, Ye Jie, Rojas Frank R, Vilar Eduardo, Maitra Anirban, Chen Ken, Navin Nicolas, Nilsson Monique, Huang Beibei, Heeke Simon, Zhang Jianhua, Haymaker Cara L, Velcheti Vamsidhar, Sterman Daniel H, Kochat Veena, Padron William I, Alexandrov Ludmil B, Wei Zhubo, Le Xiuning, Wang Linghua, Fukuoka Junya, Lee J Jack, Wistuba Ignacio I, Pass Harvey I, Davis Mark, Hanash Samir, Cheng Chao, Dubinett Steven, Spira Avrum, Rai Kunal, Lippman Scott M, Futreal P Andrew, Heymach John V, Reuben Alexandre, Wu Jia, Zhang Jianjun
How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

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