Abstract
Macrophages are tissue-resident cells that act as immune sentinels to maintain tissue integrity, preserve self-tolerance and protect against invading pathogens. Lung macrophages within the distal airways face around 8000–9000 L of air every day and for that reason are continuously exposed to a variety of inhaled particles, allergens or airborne microbes. Chronic exposure to irritant particles can prime macrophages to mediate a smoldering inflammatory response creating a mutagenic environment and favoring cancer initiation. Tumor-associated macrophages (TAMs) represent the majority of the tumor stroma and maintain intricate interactions with malignant cells within the tumor microenvironment (TME) largely influencing the outcome of cancer growth and metastasis. A number of macrophage-centered approaches have been investigated as potential cancer therapy and include strategies to limit their infiltration or exploit their antitumor effector functions. Recently, strategies aimed at targeting IL-1β signaling pathway using a blocking antibody have unexpectedly shown great promise on incident lung cancer. Here, we review the current understanding of the bridge between TAM metabolism, IL-1β signaling, and effector functions in lung adenocarcinoma and address the challenges to successfully incorporating these pathways into current anticancer regimens.
Highlights
Lung cancer is the leading cause of cancer-related death and the second most common malignancy with non-small cell lung cancer (NSCLC) referring for lung adeno and squamous carcinomas and accounting for up to 80% of all newly diagnosed lung cancer cases [1,2]
We describe recent advances made on the ontogeny of lung resident macrophages and their expansion and metabolic rewiring towards the lung cancer supporting tumor-associated macrophages (TAMs) phenotype, which depend on a specialized tumor microenvironment (TME)
Using single-cell and mass cytometry by time of-flight (CyTOF) analyses in early human lung adenocarcinomas, the group of Merad identified a unique tumor-specific macrophage population that dissociated from tissue-resident macrophages (Figure 2, left panel) [86]. These Resident Tumor-Associated Macrophages (rTAMs) exhibited an upregulation of transcripts involved in macrophage effector functions such as triggering receptor expressed on myeloid cells-2 (TREM2), tetraspanin CD81 or macrophage receptor with collagenous structure (MARCO) that were associated with a significant survival disadvantage [86]
Summary
Lung cancer is the leading cause of cancer-related death and the second most common malignancy with non-small cell lung cancer (NSCLC) referring for lung adeno and squamous carcinomas and accounting for up to 80% of all newly diagnosed lung cancer cases [1,2]. The overall five-year survival rate among newly diagnosed lung cancer patients remains in the low range of 15% [3]. When the host is chronically challenged, upon chronic exposure to irritant particles or infection, for example, macrophages may play a detrimental role contributing to a low-grade inflammatory state that leads to disease progression or even cancer initiation [21,22]. This is illustrated by the increased lung cancer risk in smokers and patients with chronic obstructive pulmonary disease (COPD). We further outline the contribution of the IL-1β signaling pathway, and how its metabolic-dependent modulation in TAMs could explain part of the anti-tumorigenic potential of IL-1β inhibition
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