
pmid: 38581685
pmc: PMC11145179
Abstract Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis. Significance: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897
Male, Lung Neoplasms, T-Lymphocytes, FOS: Clinical medicine, Immunology, 610, Cell Biology, Tumour Biology, Imaging, Signalling & Oncogenes, Tumor Microenvironment, Humans, Myeloid Cells, Female, Genetics & Genomics, Research Articles, Immune Evasion, Computational & Systems Biology
Male, Lung Neoplasms, T-Lymphocytes, FOS: Clinical medicine, Immunology, 610, Cell Biology, Tumour Biology, Imaging, Signalling & Oncogenes, Tumor Microenvironment, Humans, Myeloid Cells, Female, Genetics & Genomics, Research Articles, Immune Evasion, Computational & Systems Biology
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| influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | Top 10% | |
| impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network. | Top 1% |
