Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

Authors

Zheng Gong, The Jackson LaboratoryFollow
Qing Li, The Jackson LaboratoryFollow
Jiayuan Shi, The Jackson LaboratoryFollow
Jian Wei, The Jackson LaboratoryFollow
Peishan Li, The Jackson LaboratoryFollow
Chih-Hao Chang, The Jackson LaboratoryFollow
Leonard D. Shultz, The Jackson LaboratoryFollow
Guangwen Ren, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

8-9-2022

Publication Title

Immunity

Keywords

JMG, PGE2, breast cancer, dendritic cells, fibroblasts, immune dysfunction, immunosuppression, immunotherapeutics, lung metastasis, monocytes, pre-metastatic niche

JAX Source

Immunity . 2022 Aug 9;55(8):1483-1500.e9.

Volume

55

Issue

8

First Page

1483

Last Page

1500000000000

PMID

35908547

DOI

10.1016/j.immuni.2022.07.001

Grant

We thank Dr. Scott I. Abrams (Roswell Park Comprehensive Cancer Center) for providing the AT3 cell line and Dr. Robert A. Weinberg (MIT) for providing the lentiviral vector expressing the mouse G-CSF. This work was supported by NIH grants (R00-CA188093, R37-CA237307, R01-CA251433, and P30- CA034196 to G.R., and R24-OD026440 to L.D.S.). Z.G. is supported by the Brooks Scholar Award Program at The Jackson Laboratory. We appreciate Dr. Iiro Taneli Helenius for his critical editing of the manuscript, Drs. Edison T. Liu, Karolina Palucka, Nadia A. Rosenthal, and David V. Serreze for their insightful advice during the project, and also thank the assistance from The Jackson Laboratory Scientific Service.

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.

Recommended Citation

Gong Z, Li Q, Shi J, Wei J, Li P, Chang C, Shultz LD, Ren G. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment Immunity . 2022 Aug 9;55(8):1483-1500.e9.