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; 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; Anirban Maitra; Ken Chen; Nicolas Navin; Monique Nilsson; Beibei Huang; Simon Heeke; Jianhua Zhang; Cara L. Haymaker; Vamsidhar Velcheti; Daniel H. Sterman; Veena Kochat; William I. Padron; Ludmil B. Alexandrov; Zhubo Wei; Xiuning Le; Linghua Wang; Junya Fukuoka; J. Jack Lee; Ignacio I. Wistuba; Harvey I. Pass; Mark Davis; Samir Hanash; Chao Cheng; Steven Dubinett; Avrum Spira; Kunal Rai; Scott M. Lippman; P. Andrew Futreal; John V. Heymach; Alexandre Reuben; Jia Wu; Jianjun Zhang

doi:10.1016/j.ccell.2025.04.003

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, 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 VilarAnirban Maitra, Ken Chen, Nicolas Navin, Monique Nilsson, Beibei Huang, Simon Heeke, Jianhua Zhang, Cara L. Haymaker, Vamsidhar Velcheti, Daniel H. Sterman, Veena Kochat, William I. Padron, Ludmil B. Alexandrov, Zhubo Wei, Xiuning Le, Linghua Wang, Junya Fukuoka, J. Jack Lee, Ignacio I. Wistuba, Harvey I. Pass, Mark Davis, Samir Hanash, Chao Cheng, Steven Dubinett, Avrum Spira, Kunal Rai, Scott M. Lippman, P. Andrew Futreal, John V. Heymach, Alexandre Reuben, Jia Wu, Jianjun Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

4 Scopus citations

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.

Original language	English
Pages (from-to)	1125-1140.e10
Journal	Cancer Cell
Volume	43
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2025.04.003
State	Published - 09 06 2025
Externally published	Yes

Bibliographical note

Keywords

TIM-3
cancer prevention
imaging mass cytometry
immune landscape
lung adenocarcinoma evolution
precancer
spatial single cell
stage dependent
Humans
Adenocarcinoma of Lung/genetics
Multiomics
Gene Expression Profiling
Immunity, Innate
Precancerous Conditions/genetics
Lung Neoplasms/genetics
Animals
Tumor Microenvironment/immunology
Mice
Single-Cell Analysis
Hepatitis A Virus Cellular Receptor 2/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2025.04.003

Cite this

Zhu, B., Chen, P., Aminu, M., Li, J. R., Fujimoto, J., Tian, Y., Hong, L., Chen, H., Hu, X., Li, C., Vokes, N., Moreira, A. L., Gibbons, D. L., Solis Soto, L. M., Parra Cuentas, E. R., Shi, O., Diao, S., Ye, J., Rojas, F. R., ... Zhang, J. (2025). Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception. Cancer Cell, 43(6), 1125-1140.e10. https://doi.org/10.1016/j.ccell.2025.04.003

@article{ec92ef33f51e48e7a74cfb7f6df9e874,

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

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.",

keywords = "TIM-3, cancer prevention, imaging mass cytometry, immune landscape, lung adenocarcinoma evolution, precancer, spatial single cell, stage dependent, Humans, Adenocarcinoma of Lung/genetics, Multiomics, Gene Expression Profiling, Immunity, Innate, Precancerous Conditions/genetics, Lung Neoplasms/genetics, Animals, Tumor Microenvironment/immunology, Mice, Single-Cell Analysis, Hepatitis A Virus Cellular Receptor 2/genetics",

author = "Bo Zhu and Pingjun Chen and Muhammad Aminu and Li, \{Jian Rong\} and Junya Fujimoto and Yanhua Tian and Lingzhi Hong and Hong Chen and Xin Hu and Chenyang Li and Natalie Vokes and Moreira, \{Andre L.\} and Gibbons, \{Don L.\} and \{Solis Soto\}, \{Luisa M.\} and \{Parra Cuentas\}, \{Edwin Roger\} and Ou Shi and Songhui Diao and Jie Ye and Rojas, \{Frank R.\} and Eduardo Vilar and Anirban Maitra and Ken Chen and Nicolas Navin and Monique Nilsson and Beibei Huang and Simon Heeke and Jianhua Zhang and Haymaker, \{Cara L.\} and Vamsidhar Velcheti and Sterman, \{Daniel H.\} and Veena Kochat and Padron, \{William I.\} and Alexandrov, \{Ludmil B.\} and Zhubo Wei and Xiuning Le and Linghua Wang and Junya Fukuoka and Lee, \{J. Jack\} and Wistuba, \{Ignacio I.\} and Pass, \{Harvey I.\} and Mark Davis and Samir Hanash and Chao Cheng and Steven Dubinett and Avrum Spira and Kunal Rai and Lippman, \{Scott M.\} and Futreal, \{P. Andrew\} and Heymach, \{John V.\} and Alexandre Reuben and Jia Wu and Jianjun Zhang",

year = "2025",

month = jun,

day = "9",

doi = "10.1016/j.ccell.2025.04.003",

language = "英语",

volume = "43",

pages = "1125--1140.e10",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

Zhu, B, Chen, P, Aminu, M, Li, JR, Fujimoto, J, Tian, Y, Hong, L, Chen, H, Hu, X, Li, C, Vokes, N, Moreira, AL, Gibbons, DL, Solis Soto, LM, Parra Cuentas, ER, Shi, O, Diao, S, Ye, J, Rojas, FR, Vilar, E, Maitra, A, Chen, K, Navin, N, Nilsson, M, Huang, B, Heeke, S, Zhang, J, Haymaker, CL, Velcheti, V, Sterman, DH, Kochat, V, Padron, WI, Alexandrov, LB, Wei, Z, Le, X, Wang, L, Fukuoka, J, Lee, JJ, Wistuba, II, Pass, HI, Davis, M, Hanash, S, Cheng, C, Dubinett, S, Spira, A, Rai, K, Lippman, SM, Futreal, PA, Heymach, JV, Reuben, A, Wu, J & Zhang, J 2025, 'Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception', Cancer Cell, vol. 43, no. 6, pp. 1125-1140.e10. https://doi.org/10.1016/j.ccell.2025.04.003

TY - JOUR

T1 - Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception

AU - Zhu, Bo

AU - Chen, Pingjun

AU - Aminu, Muhammad

AU - Li, Jian Rong

AU - Fujimoto, Junya

AU - Tian, Yanhua

AU - Hong, Lingzhi

AU - Chen, Hong

AU - Hu, Xin

AU - Li, Chenyang

AU - Vokes, Natalie

AU - Moreira, Andre L.

AU - Gibbons, Don L.

AU - Solis Soto, Luisa M.

AU - Parra Cuentas, Edwin Roger

AU - Shi, Ou

AU - Diao, Songhui

AU - Ye, Jie

AU - Rojas, Frank R.

AU - Vilar, Eduardo

AU - Maitra, Anirban

AU - Chen, Ken

AU - Navin, Nicolas

AU - Nilsson, Monique

AU - Huang, Beibei

AU - Heeke, Simon

AU - Zhang, Jianhua

AU - Haymaker, Cara L.

AU - Velcheti, Vamsidhar

AU - Sterman, Daniel H.

AU - Kochat, Veena

AU - Padron, William I.

AU - Alexandrov, Ludmil B.

AU - Wei, Zhubo

AU - Le, Xiuning

AU - Wang, Linghua

AU - Fukuoka, Junya

AU - Lee, J. Jack

AU - Wistuba, Ignacio I.

AU - Pass, Harvey I.

AU - Davis, Mark

AU - Hanash, Samir

AU - Cheng, Chao

AU - Dubinett, Steven

AU - Spira, Avrum

AU - Rai, Kunal

AU - Lippman, Scott M.

AU - Futreal, P. Andrew

AU - Heymach, John V.

AU - Reuben, Alexandre

AU - Wu, Jia

AU - Zhang, Jianjun

PY - 2025/6/9

Y1 - 2025/6/9

N2 - 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.

AB - 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.

KW - TIM-3

KW - cancer prevention

KW - imaging mass cytometry

KW - immune landscape

KW - lung adenocarcinoma evolution

KW - precancer

KW - spatial single cell

KW - stage dependent

KW - Humans

KW - Adenocarcinoma of Lung/genetics

KW - Multiomics

KW - Gene Expression Profiling

KW - Immunity, Innate

KW - Precancerous Conditions/genetics

KW - Lung Neoplasms/genetics

KW - Animals

KW - Tumor Microenvironment/immunology

KW - Mice

KW - Single-Cell Analysis

KW - Hepatitis A Virus Cellular Receptor 2/genetics

UR - https://www.scopus.com/pages/publications/105006830352

U2 - 10.1016/j.ccell.2025.04.003

DO - 10.1016/j.ccell.2025.04.003

M3 - 文章

C2 - 40345189

AN - SCOPUS:105006830352

SN - 1535-6108

VL - 43

SP - 1125-1140.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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