Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception
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.
Authors
- Jia Wu (ORCID: https://orcid.org/0000-0001-8392-8338)
- Don L. Gibbons (ORCID: https://orcid.org/0000-0003-2362-3094)
- Simon Heeke (ORCID: https://orcid.org/0000-0002-5916-534X)
- Nicolas Navin
- Daniel H. Sterman (ORCID: https://orcid.org/0009-0004-0170-2722)
- Mark M. Davis (ORCID: https://orcid.org/0000-0001-6868-657X)
- Beibei Huang (ORCID: https://orcid.org/0000-0003-0555-6924)
- Ignacio I. Wistuba (ORCID: https://orcid.org/0000-0003-3365-6340)
- Xin Hu (ORCID: https://orcid.org/0000-0003-1097-3300)
- Lingzhi Hong (ORCID: https://orcid.org/0000-0001-6553-3279)
- William Padron
- Veena Kochat (ORCID: https://orcid.org/0000-0003-2614-3790)
- André L. Moreira (ORCID: https://orcid.org/0000-0003-1857-3774)
- Samir Hanash (ORCID: https://orcid.org/0000-0002-4210-1593)
- Monique B. Nilsson (ORCID: https://orcid.org/0000-0002-0975-8833)
- Junya Fukuoka (ORCID: https://orcid.org/0000-0002-2496-3050)
- Edwin R. Parra (ORCID: https://orcid.org/0000-0001-9068-1636)
- Pingjun Chen (ORCID: https://orcid.org/0000-0003-0528-1713)
- Chenyang Li (ORCID: https://orcid.org/0000-0002-9144-5827)
- John Victor Heymach (ORCID: https://orcid.org/0000-0001-9068-8942)
- Zhubo Wei (ORCID: https://orcid.org/0000-0003-4495-3527)
- Cara Haymaker (ORCID: https://orcid.org/0000-0002-1317-9287)
- Linghua Wang (ORCID: https://orcid.org/0000-0001-9380-0266)
- Muhammad Aminu (ORCID: https://orcid.org/0000-0002-9903-8812)
- Eduardo Vilar (ORCID: https://orcid.org/0000-0001-6404-3761)
- Avrum Spira
- Vamsidhar Velcheti (ORCID: https://orcid.org/0000-0002-6589-0759)
- P. Andrew Futreal (ORCID: https://orcid.org/0000-0001-8663-2671)
- Jianhua Zhang (ORCID: https://orcid.org/0000-0003-2528-6132)
- Songhui Diao (ORCID: https://orcid.org/0000-0002-0971-8591)
- Scott M. Lippman (ORCID: https://orcid.org/0000-0002-1643-4124)
- J. Jack Lee
- Kunal Rai (ORCID: https://orcid.org/0000-0003-2321-6894)
- Frank Rojas (ORCID: https://orcid.org/0000-0003-2605-435X)
- Yanhua Tian
- Luisa M. Solis Soto (ORCID: https://orcid.org/0000-0002-1253-630X)
- Ludmil B. Alexandrov (ORCID: https://orcid.org/0000-0003-3596-4515)
- Junya Fujimoto (ORCID: https://orcid.org/0000-0003-4813-3163)
- Alexandre Reuben (ORCID: https://orcid.org/0000-0003-4510-0382)
- Natalie I. Vokes (ORCID: https://orcid.org/0000-0002-3766-5335)
- Ou Shi
- Harvey I. Pass (ORCID: https://orcid.org/0000-0003-3222-3471)
- Jie Ye (ORCID: https://orcid.org/0009-0003-4323-1079)
- Ken Chen (ORCID: https://orcid.org/0000-0003-4013-5279)
- Hong Chen (ORCID: https://orcid.org/0000-0001-8054-7417)
- Bo Zhu (ORCID: https://orcid.org/0000-0001-9817-3855)
- Jiànróng Lǐ (ORCID: https://orcid.org/0000-0002-7130-1084)
- Chao Cheng (ORCID: https://orcid.org/0009-0002-9586-2131)
- Anirban Maitra (ORCID: https://orcid.org/0000-0003-0298-9775)
- Steven M. Dubinett
- Jianjun Zhang (ORCID: https://orcid.org/0000-0001-7872-3477)
- Xiuning Le
Institutions
- Boston University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- Baylor College of Medicine (US)
- University of California San Diego (US)
- NYU Langone Health (US)
- Hiroshima University Hospital (JP)
- Nagasaki University (JP)
- New York University (US)
- Stanford University (US)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1016/j.ccell.2025.04.003
- Citations
- 23
- Primary Topic
- Galectins and Cancer Biology
- Type
- article
- Field-Weighted Citation Impact
- 18.34