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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-05-08 DOI:10.1016/j.ccell.2025.04.003

Bo Zhu, Pingjun Chen, Muhammad Aminu, Jian-Rong Li, Junya Fujimoto, Yanhua Tian, Lingzhi Hong, Hong Chen, Xin Hu, Chenyang Li, Natalie Vokes, Andre L. Moreira, Don L. Gibbons, Luisa M. Solis Soto, Edwin Roger Parra Cuentas, Ou Shi, Songhui Diao, Jie Ye, Frank R. Rojas, Eduardo Vilar, Jianjun Zhang

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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.

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人类和小鼠肺腺癌前体的空间和多组学分析显示，TIM-3可能是癌前阻断的靶点

肿瘤微环境如何塑造肺腺癌（LUAD）的癌前进化仍然知之甚少。114种人类LUAD和LUAD前体的空间免疫分析显示，随着LUAD前体的进展，适应性反应逐渐增加，先天免疫反应相对减少。免疫逃避特征使免疫反应模式在不同阶段保持一致。TIM-3-high特征在LUAD癌前病变中丰富，在晚期减少。此外，来自5种小鼠模型的LUAD和LUAD前体标本的单细胞RNA测序（scRNA-seq）和空间免疫和转录组学分析证实了LUAD癌前病变的高TIM-3特征。体内TIM-3阻断在癌前期，而不是在晚期，降低肿瘤负荷。抗tim -3治疗与抗原呈递增强、T细胞活化和M1/M2巨噬细胞比例增加有关。这些结果强调了LUAD癌前发展过程中先天和适应性免疫反应/逃避的协调，并提示TIM-3可能是LUAD癌前阻断的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.