Alveolar macrophages maintain tissue localization and gain enhanced anti-tumor activity in Lewis lung carcinoma-reprogrammed lung microenvironment

TL;DR

Alveolar macrophages remain active and anti-tumor in lung cancer-affected areas, despite being separated from the tumor itself.

Contribution

This study reveals that alveolar macrophages retain and enhance anti-tumor activity in the lung microenvironment adjacent to tumors.

Findings

Alveolar macrophages avoid tumor lesions but remain active in the surrounding lung tissue.

AMs show increased activation markers and improved phagocytic abilities in the tumor-adjacent lung.

AMs retain lipid metabolism and responsiveness, and demonstrate enhanced anti-tumor function.

Abstract

The role of alveolar macrophages (AMs) in lung carcinogenesis has been extensively studied, yielding significant insights. However, the status of AMs in tumor-bearing lungs remains incompletely characterized. Using orthotopic Lewis Lung Carcinoma (LLC) mouse models, we found that tumors induced an inflammatory extra-tumoral lung microenvironment (ETLME), distinct from the immunosuppressive tumor microenvironment (TME). T cells with an exhaustion phenotype and tumor-associated macrophages (TAMs) mainly accumulated in the TME rather than the ETLME. Surprisingly, AMs were absent from the tumor lesions and remained in the lung tissues, but they displayed a more active dynamic balance between proliferation and death in ETLME. Furthermore, AMs presented an activated phenotype characterized by upregulation of CD11b and downregulation of Siglec-F, elevated expression of inflammatory genes, and enhanced phagocytic and efferocytotic activity. Notably, AMs in ETLME retained their lipid metabolism capacity and responsiveness to external stimuli. More importantly, LLC-experienced AMs display enhanced anti-tumor ability. These findings indicate that AMs maintain their tissue localization and functional integrity within the ETLME.

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