Taking the good with the bad

Macrophage functional identity is, in part, dependent on their origin. Tissue-resident macrophages (TRMs) are locally self-renewing cells involved in the maintenance of tissue-specific homeostasis and inflammation. TRMs are mostly seeded during embryonic development, whereas monocyte-derived macrophages (MDMs) arise from adult hematopoietic stem cells (HSCs) and are recruited to inflamed sites from the peripheral blood. Although macrophages are known to influence cancer progression, the specific contributions of TRM and MDM to tumorigenesis are poorly defined.

Cassanova-Acebes et al. explored the spatial and temporal distribution of TRMs and MDMs in the tumor microenvironment and defined their functional contributions to tumor progression. They analyzed single-cell RNA-seq data and defined analogous clusters of macrophages and monocytes in (i) early-stage, treatment-naïve human non-small cell lung carcinoma (NSCLC) lesions and (ii) lung tumors from an orthotopic mouse model injected with Kras^G12D and p53-deficient (KP) cells. Fate mapping of cells expressing MAP17, a signature molecule of adult HSCs, indicated that the major macrophage clusters show distinct ontogeny, TRMs and MDMs, and molecular signatures. The authors used these molecular and phenotypic signatures to investigate the spatial interactions between TRMs and tumor cells during early tumor expansion. They found that TRMs initially localized in close proximity to tumor cells and subsequently migrated to the periphery as the tumors expanded.

The authors evaluated the impact of TRMs on cancer cells during early tumor progression. Using 3D spheroid and transwell systems, KP cells cultured with TRMs showed greater tumor cell migration and invasion and expressed genes associated with epithelial-mesenchymal transition. KP cells cultured in the presence of TRMs also expressed VEGFA and urokinase-type plasminogen activator, which promote the differentiation of T_reg cells. The depletion of TRM from early tumor lesions in vivo using a CD169-diphteria toxin receptor model caused a reduction in tumor-localized T_reg cells, an increase in CD8⁺ T cell to T_reg cell ratio, and a decrease in tumor volumes. Interestingly, depletion of TRM from established tumors had no effect on these parameters.

This study supports a critical role for TRMs in promoting early tumorigenesis in the lung via the induction of tumor invasiveness, EMT, and immunosuppression by T_reg cells. The authors nominate TRMs as potential therapeutic targets in the treatment of early NSCLC. These findings warrant further validation in additional tissue sites to determine whether the pro-tumorigenic role of TRM is conserved across cancer types of diverse histologies and tissue microenvironments.

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