Zhu et al. demonstrated a coordinated interplay between innate and adaptive immunity during the initiation and progression of LUAD pre-cancers, revealing stage-specific remodeling of the tumor microenvironment, including shifts in macrophage polarization and T lymphocyte differentiation. TIM-3 expression increased at early phases of carcinogenesis in human LUAD and in 5 genetically distinct LUAD mouse models. Anti-TIM-3 treatment shifted M1/M2 macrophage polarization, enhanced antigen presentation by DCs, increased T cell activation and cytotoxicity, and decreased tumor burden at pre-cancer, but not advanced cancer stages.
Contributed by Shishir Pant
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.
Author Info: (1) 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 Te
Author Info: (1) 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. (2) 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. (3) Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Medicine, Baylor College of Medicine, Houston, TX, USA. (5) Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima, Japan. (6) 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. (7) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) 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. (9) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Pathology, NYU Langone Health, New York, NY, USA. (13) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Translational Molecular Pathology and Sheikn Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA. (30) Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA; Cardiothoracic Surgery, NYU Grossman School of Medicine, New York, NY, USA. (31) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA. (34) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (35) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (36) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (37) Department of Pathology Informatics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. (38) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (39) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (40) Department of Cardiothoracic Surgery, NYU Langone Health, New York, NY, USA. (41) Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA. (42) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, CA, USA. (43) Department of Medicine, Baylor College of Medicine, Houston, TX, USA. (44) Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (45) Pathology & Laboratory Medicine, and Bioinformatics, Boston University, Boston, MA, USA. (46) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (47) UC San Diego School of Medicine, La Jolla, CA, USA. (48) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (50) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (51) Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (52) 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. Electronic address: jzhang20@mdanderson.org.
