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
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Cell. 2025 Jun 9;43(6):1125-1140.e10. doi: 10.1016/j.ccell.2025.04.003. Epub 2025 May 8.
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.
肿瘤微环境如何塑造肺腺癌(LUAD)癌前病变的演变仍知之甚少。对114例人类LUAD及其癌前病变进行空间免疫分析发现,随着LUAD癌前病变的进展,适应性反应逐渐增加,而固有免疫反应相对减少。免疫逃逸特征使不同阶段的免疫反应模式趋于一致。TIM-3高表达特征在LUAD癌前病变中富集,而在后期阶段减少。此外,对来自5个小鼠模型的LUAD及其癌前病变样本进行单细胞RNA测序(scRNA-seq)以及空间免疫和转录组学分析,证实了LUAD癌前病变中TIM-3高表达特征。在癌前阶段而非晚期癌症阶段进行体内TIM-3阻断可减轻肿瘤负担。抗TIM-3治疗与增强抗原呈递、T细胞活化以及增加M1/M2巨噬细胞比例有关。这些结果突出了LUAD癌前病变演变过程中固有免疫和适应性免疫反应/逃逸的协调作用,并提示TIM-3作为LUAD癌前病变拦截的潜在靶点。