Abstract
Macrophage embryonic lineage contributes to invasiveness and immune evasion at the onset of tumorigenesis.
Major Finding: Macrophage embryonic lineage contributes to invasiveness and immune evasion at the onset of tumorigenesis.
Concept: Tissue-residing macrophages dominate early and then redistribute upon monocyte-derived macrophage infiltration.
Impact: Targeting tissue-resident macrophages could be a promising early therapeutic strategy for lung cancers.
Macrophages are an important component of the tumor microenvironment (TME), with roles in tumor immunity and response to immunotherapy. Therapeutic targeting of macrophages has significant potential, but current knowledge about the diversity and functions of tumor-associated macrophages is lacking. Using single-cell RNA sequencing, Casanova-Acebes, Dalla, and colleagues analyzed samples of tumor and nonmalignant lung from 35 people with early-stage non–small cell lung cancer along with samples from murine models of lung adenocarcinoma, finding four distinct clusters of monocytes and macrophages with differing gene expression profiles. Lineage tracing of these macrophage populations using two different murine models revealed distinct spatial and temporal distributions in the TME as well as different origins, with some being locally self-maintained tissue-resident macrophage (TRM) populations whereas others were monocyte-derived macrophages derived from adult hematopoietic stem cells in the bone marrow. Coculture of mouse adenocarcinoma cells with TRMs caused distinct transcriptional changes, promoted invasion and epithelial–mesenchymal transition, and increased the dispersion of tumor cells over time. Coculture of the same cells with monocyte-derived macrophages instead resulted in changes in genes associated with DNA replication and cell-cycle regulation. TRMs were located close to tumor cells in early-stage lung lesions along with an accumulation of T regulatory cells but were found increasingly at the TME periphery as tumors grew and the population of monocyte-derived macrophages increased. Specific depletion of TRMs using an engineered mouse model reduced regulatory T cells, promoted CD8+ T-cell recruitment and reduced tumor growth and invasion. The authors suggest that TRMs play a key role in the progression of early-stage lung tumors and that targeting TRMs could be an effective therapeutic strategy for the treatment and prevention of these lesions.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
RSS Feeds