Gong and Li et al. described a COX-2+ lung adventitial fibroblast population, constitutively expressing high levels of inflammatory genes, that induced myeloid cells to be dysfunctional or immunosuppressive, fostering a pre-metastatic lung niche at steady state and enhanced by a distal tumor. In murine breast cancer models, COX-2 gene deletion in fibroblasts reversed myeloid cell dysfunction induced by IL-1β, PGE2, and other tumor-associated inflammation; boosted immune activation; and decreased lung metastasis. Genetic or pharmacologic inhibition of the PGE2 signaling pathway enhanced anti-metastatic activities of DC-based vaccines or PD-1 blockade.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (2) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (3) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (4) The Jackson
Author Info: (1) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (2) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (3) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (4) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (5) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (6) The Jackson Laboratory, Bar Harbor, ME 04609, USA; Tufts University School of Medicine, Boston, MA 02111, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA. (7) The Jackson Laboratory, Bar Harbor, ME 04609, USA. (8) The Jackson Laboratory, Bar Harbor, ME 04609, USA; Tufts University School of Medicine, Boston, MA 02111, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA. Electronic address: gary.ren@jax.org.
