Macrophages of distinct origins contribute to tumor development in the lung

Abstract

Tissue-resident macrophages can self-maintain without contribution of adult hematopoiesis. Herein we show that tissue-resident interstitial macrophages (Res-TAMs) in mouse lungs contribute to the pool of tumor-associated macrophages (TAMs) together with CCR2-dependent recruited macrophages (MoD-TAMs). Res-TAMs largely correlated with tumor cell growth in vivo, while MoD-TAMs accumulation was associated with enhanced tumor spreading. Both cell subsets were depleted after chemotherapy, but MoD-TAMs rapidly recovered and performed phagocytosis-mediated tumor clearance. Interestingly, anti-VEGF treatment combined with chemotherapy inhibited both Res and Mod-TAM reconstitution without affecting monocyte infiltration and improved its efficacy. Our results reveal that the developmental origin of TAMs dictates their relative distribution, function, and response to cancer therapies in lung tumors.

A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages

“…Tissue-resident interstitial macrophages (CD64 + Siglec F − ) have recently been reported to contribute to the population of tumour-associated macrophages [12]. To exclude the possibility that these tissue-resident peribronchial or perivascular interstitial macrophages can migrate to the alveolar space in response to asbestos-induced epithelial injury and differentiate into alveolar macrophages, we treated Cx3cr1 ER-Cre ×ZsGreen reporter mice with tamoxifen to label tissue-resident interstitial macrophages (figure 2d).…”

“…Tissue-resident alveolar macrophages originate from fetal monocytes, populate the alveolar niche soon after birth, are capable of self-renewal and, in mouse models, persist in the lung without appreciable input from myeloid cells over the lifespan of the animal [7][8][9][10]. Lung tissue-resident interstitial macrophages have been shown to include perivascular and peribronchial macrophages, which demonstrate distinct anatomical localisation and function [11][12][13][14]. In response to alveolar macrophage depletion and/or injury, monocytes are recruited to the lung where factors present in the microenvironment drive their differentiation into alveolar macrophages [15,16].…”

Monocyte heterogeneity and functions in cancer

“…TAMs can be proliferative, which could provide a compensatory mechanism when monocyte recruitment is impaired . Recent work has demonstrated that in lung metastatic sites, TAMs are derived from both CCR2‐dependent monocytes and resident interstitial Mϕs, each promoting tumor growth and metastatic spreading, respectively . Additional work is needed to better understand the relative contributions of monocytes and resident Mϕ populations to TAM accumulation and phenotype across different tumor types.…”

Contribution of Macrophages and T Cells in Skeletal Metastasis

“…The majority of macrophages present in the tumor microenvironment are recruited from bone marrow-derived monocytes through the CC chemokine 2 (CCL2/CCR2) [28][29][30][31] and colony stimulating factor 1 (CSF-1/CSF-1R) [32] signaling pathways. However, studies have identified a mixture of yolk sac-derived and bone marrow-derived macrophages in the tumor microenvironment suggesting that, depending on their origin, TAMs have different roles during tumor progression [33][34][35]. TAMs secrete inflammatory cytokines, growth factors and proteolytic enzymes that promote cell proliferation, invasion, and angiogenesis [7,36,37].…”