Editors' ChoiceCancer

Filled with Evil: Molecular Signatures of Tumor-Associated Immune Cells

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Science Translational Medicine  03 Dec 2014:
Vol. 6, Issue 265, pp. 265ec207
DOI: 10.1126/scitranslmed.aaa3408

Tumor-associated macrophages (TAMs) are one of the main inflammatory cell types present in many solid tumors in mice, where they can either promote or restrict tumor growth. The characteristics of TAMs in humans and whether they contribute to human cancer progression is not so clear.

Now, Chittezhath et al. have combined functional assays with transcriptomic analysis to investigate immune cells in human renal cell carcinoma (RCC), a common kidney cancer characterized by few early symptoms and a high rate of metastasis. Compared with those of healthy controls, the transcriptomic profiles for blood monocytes of 14 patients with RCC displayed upregulation of many proinflammatory cytokines and chemokines, as well as of key protumor genes. The monocyte’s apparent proinflammatory and tumor-promoting phenotype was confirmed in vitro. Further, RCC tumor cells conditioned human monocytes to adopt the inflammatory and protumor phenotype through interleukin-1β (IL-1β) via an IL-1 receptor (IL-1R), myeloid differentiation marker 88 (MyD88), and nuclear factor κB (NFκB)–dependent pathway.

In mice with xenografts of human RCC, the authors demonstrated that TAMs originated from blood inflammatory monocytes and that disrupting IL-1signaling altered the TAM protumor phenotype and limited tumor growth in vivo. Furthermore, in a cohort of 34 RCC patients, IL-1β expression positively correlated with RCC cancer stage and the expression of monocyte and macrophage markers and protumor genes. Last, TAMs isolated from RCC patient tumors showed elevated protumor gene expression and exhibited enhanced protumor functions in vitro compared with macrophages from health donors.

These results establish that monocytes and macrophages found within human RCC express a protumor phenotype. IL-1β signaling through its receptor drives the tumor-promoting function of these immune cells and may be a potential therapeutic target for RCC and perhaps other types of cancer.

M. Chittezhath et al., Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression. Immunity 411, 815–829 (2014). [Abstract]

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