Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment.

Zaynagetdinov R, Sherrill TP, Gleaves LA, McLoed AG, Saxon JA, Habermann AC, Connelly L, Dulek D, Peebles RS, Fingleton B, Yull FE, Stathopoulos GT, Blackwell TS
Cancer Res. 2015 75 (8): 1624-1634

PMID: 25691457 · PMCID: PMC4401663 · DOI:10.1158/0008-5472.CAN-14-2379

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.

©2015 American Association for Cancer Research.

MeSH Terms (15)

Animals Carcinoma, Lewis Lung Cell Line, Tumor Eosinophils Female Interleukin-5 Lung Lung Neoplasms Male Mice Mice, Inbred C57BL Mice, Knockout T-Lymphocytes, Regulatory Tumor Escape Tumor Microenvironment

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