title: Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment.
abstract: Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine involved in allergic and infectious diseases, facilitates metastatic colonization through recruitment of sentinel eosinophils and regulation of other inflammatory/immune cells in the microenvironment of the distal lung. Genetic IL5 deficiency offered marked protection of the lungs from metastasis of different types of tumor cells, including lung cancer, melanoma, and colon cancer. IL5 neutralization protected subjects from metastasis, whereas IL5 reconstitution or adoptive transfer of eosinophils into IL5-deficient mice exerted prometastatic effects. However, IL5 deficiency did not affect the growth of the primary tumor or the size of metastatic lesions. Mechanistic investigations revealed that eosinophils produce CCL22, which recruits regulatory T cells to the lungs. During early stages of metastasis, Treg created a protumorigenic microenvironment, potentially by suppressing IFNγ-producing natural killer cells and M1-polarized macrophages. Together, our results establish a network of allergic inflammatory circuitry that can be co-opted by metastatic cancer cells to facilitate lung colonization, suggesting interventions to target this pathway may offer therapeutic benefits to prevent or treat lung metastasis.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Allyson G
authors.initials: AG
authors.lastname: McLoed
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Saxon
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Arun C
authors.initials: AC
authors.lastname: Habermann
authors.affiliation: Department of Pharmaceutical Sciences, University of Hawaii, Hilo, Hawaii, USA, 96720.
authors.forename: Linda
authors.initials: L
authors.lastname: Connelly
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dulek
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA, 37232.|U.S. Department of Veterans Affairs.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fingleton
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA, 37232.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, University of Patras, 26504 Rio, Greece.
authors.forename: Georgios T
authors.initials: GT
authors.lastname: Stathopoulos
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA, 37232.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA, 37232.|U.S. Department of Veterans Affairs.|Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA, 37232.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA, 37232.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D004804:Eosinophils / Q000473:pathology; D005260:Female; D015848:Interleukin-5 / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: D015848:Interleukin-5