Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception
Bo Zhu, Pingjun Chen, Muhammad Aminu, Jiànróng Lǐ, Junya Fujimoto, Yanhua Tian, Lingzhi Hong, Hong Chen, Xin Hu, Chenyang Li, Natalie I. Vokes, André L. Moreira, Don L. Gibbons, Luisa M. Solis Soto, Edwin R. Parra, Ou Shi, Songhui Diao, Jie Ye, Frank Rojas, Eduardo Vilar, Anirban Maitra, Ken Chen, Nicolas Navin, Monique B. Nilsson, Beibei Huang, Simon Heeke, Jianhua Zhang, Cara Haymaker, Vamsidhar Velcheti, Daniel H. Sterman, Veena Kochat, William Padron, Ludmil B. Alexandrov, Zhubo Wei, Xiuning Le, Linghua Wang, Junya Fukuoka, J. Jack Lee, Ignacio I. Wistuba, Harvey I. Pass, Mark M. Davis, Samir Hanash, Chao Cheng, Steven M. Dubinett, Avrum Spira, Kunal Rai, Scott M. Lippman, P. Andrew Futreal, John V. Heymach, Alexandre Reuben, Jia Wu, Jianjun Zhang
Abstract
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.