Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment.
Immunity 2022 Jul 30 [Online ahead of print]
Primary tumors are drivers of pre-metastatic niche formation, but the coordination by the secondary organ toward metastatic dissemination is underappreciated. Here, by single-cell RNA sequencing and immunofluorescence, we identified a population of cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lung immune microenvironment. At steady state, fibroblasts in the lungs produced prostaglandin E2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes. This lung-intrinsic stromal program was propagated by tumor-associated inflammation, particularly the pro-inflammatory cytokine interleukin-1β, supporting a pre-metastatic niche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressive phenotypes of lung-resident myeloid cells, resulting in heightened immune activation and diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastatic activity of DC-based therapy and PD-1 blockade was improved by fibroblast-specific Ptgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-resident fibroblasts reshape the local immune landscape to facilitate breast cancer metastasis.
Gong, Zheng; Li, Qing; Shi, Jiayuan; Wei, Jian; Li, Peishan; Chang, Chih-Hao; Shultz, Leonard D.; and Ren, Guangwen, "Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment." (2022). Faculty Research Ahead of Print. 334.