The presence of regulatory T (TReg) cells in breast cancer tumours marks an invasive phenotype and poor prognosis. A study published in Nature shows that, in addition to their immunosuppressive role in antitumoural responses, CD4+

TReg cells contribute to mammary tumour metastasis through the expression of receptor activator of nuclear factor-κB ligand (RANKL; also known as TNFSF11).

RANKL and its receptor, RANK (also known as TNFRSF11A), are involved in normal mammary cell proliferation and have been implicated in prostate cancer cell migration and bone metastasis, but the source of intratumoural RANKL and its role in metastasis are unknown. Thus, the authors used a mouse model of metastatic breast cancer to investigate the involvement of RANK signalling in mammary tumour metastasis. Rank+/– mice overexpressing the proto-oncogene Erbb2 in the mammary epithe-lium developed tumours with decreased RANK

expression and displayed 50% fewer lung metastases than Rank+/+ controls. In addition, silencing or blocking of RANK in an orthotopic tumour model resulted in reduced pulmonary metastasis. By contrast, RANKL administration in mice with RANK+ human or mouse mammary tumours significantly increased the metastatic incidence.

The authors report that the engagement of RANK by its ligand induces the activation of IκB kinase-α (IKKα) and thereby represses expression of the meta stasis inhibitor serpin B5 (also known as maspin). Moreover, RANKL treatment did not affect cancer cell motility or primary tumour growth, but increased the extravasation of circulating tumour cells in the lung and enhanced their survival.

So, what is the cellular source of the pro-metastatic factor RANKL in

mammary tumours? By immuno-

histochemical analysis, the authors

observed that RANKL colocal ized with the lymphoid cell marker CD5 in the breast cancer tumour stroma. Interestingly, no RANKL+ cells could be detected in tumours growing in T cell-deficient mice, suggesting that T cells are the RANKL producers. Furthermore, pulmonary metastasis was dimin-ished in CD4+ T cell-deficient mice with mammary tumours, whereas reconstitution with CD4+CD25+ T cells (which displayed substantially higher RANKL expression than CD4+CD25– T cells) rescued tumour RANKL levels and increased the incidence of metastases.

Finally, the authors observed colocalization of RANKL and the TReg cell-associated transcription factor forkhead box P3 (FOXP3) next to cancer-associated myofibro-blasts, which express the TReg cell chemo attractant CC-chemokine ligand 5 (CCL5). This suggests that CD4+ TReg cells are the main producers of RANKL in breast cancer tumours, highlighting a novel role for CD4+ TReg cells in cancer progression.

Based on their findings, the authors propose that the use of RANKL antagonists after surgical resection of primary breast tumours would inhibit the pro-metastatic effect of tumour-infiltrating TReg cells and, thus, the occurrence of metastases.

Maria Papatriantafyllou

ORIGINAL RESEARCH PAPER Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling. Nature 470, 548–553 (2011)

T U M O U R I M M U N O LO GY

Pro-metastatic TReg

cells get RANKed

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | IMMUNOLOGY VOLUME 11 | APRIL 2011

Nature Reviews Immunology | AOP, published online 11 March 2011; doi:10.1038/nri2962

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