Lung Fibroblasts Support Metastasis through Immune Microenvironment Remodeling

Organ colonization is considered the rate-limiting step of metastasis, as many defense barriers exist to block disseminated tumor cells. Understanding the process of organ colonization is critical to the development of therapies targeting metastasis; however, what role the microenvironment of the secondary organ site plays in organ colonization remains to be determined. Using the lung as a model, as it is one of the most common sites of metastasis for numerous late-stage cancers, Gong, Li, and colleagues investigated how lung-resident stromal fibroblasts contribute to formation of the premetastatic and metastatic niches. Dendritic cells (DC) have previously been shown to alter immune function in the premetastatic lung, and evaluation of the microenvironmental effects on DCs indicated low expression of MHC-I and MHC-II. Coculture of DCs with lung tissue cells, especially fibroblasts, revealed inhibition of DC MHC-I and MHC-II expression as well as their ability to uptake antigen. Secreted PGE2 working through COX-2 mediated this inhibition, and further evaluation of these Ptgs2^hi lung fibroblasts indicated that the top enriched genes in this subset were inflammation-associated genes, most of which are inducible by the proinflammatory cytokine IL1β. Additional investigation defined the IL1β–IL1R–NF-κB signaling axis as a regulator of COX-2–PGE2 lung fibroblasts, with lung-infiltrating neutrophils being the source of IL1β. Furthermore, in a model of murine breast cancer lung metastasis, loss of Ptgs2 in CD140a⁺ fibroblasts lessened the lung colonization of breast tumor cells, while dual inhibition of EP2/EP4, two murine PGE2 receptors, was also effective in controlling breast cancer lung metastasis. Moreover, targeting this signaling axis along with treatment with either a DC vaccine or immune checkpoint blockade demonstrated synergism indicating that combination therapy could be effective in managing lung metastasis. In summary, this study shows the role that COX-2–expressing lung fibroblasts play in developing the lung metastatic niche and supports targeting this pathway to improve the therapeutic management of metastasis.

Gong Z, Li Q, Shi J, Wei J, Li P, Chang CH, et al. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment. Immunity 2022;55:1483–500.e9.

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