Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling

Abstract

In a mouse model of ErbB-driven mammary tumours, Tan et al. find a role for RANKL (receptor activator of nuclear factor-κB ligand) in the formation of lung metastases. RANKL is produced by regulatory T cells infiltrating the primary tumours, and acts through its receptor RANK, which is expressed on the cancer cells. Targeting RANKL may therefore prove useful in reducing breast cancer metastases. In a mouse model of Erbb2-driven mammary tumours, this study finds a role for RANKL in the formation of lung metastases. RANKL is produced by regulatory T cells infiltrating the primary tumours and acts via its receptor RANK expressed on the cancer cells. Targeting RANKL may therefore prove useful in reducing breast cancer metastases. Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers1. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and lymphotoxin2. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy3 through inhibitor of nuclear factor-κB (IκB) kinase-α (IKK-α)4, a protein kinase that is needed for the self-renewal of mammary cancer progenitors5 and for prostate cancer metastasis2. We therefore examined whether RANKL, RANK and IKK-α are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu)6, which is frequently amplified in metastatic human breast cancers7,8, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4+CD25+ T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)+ stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK+ human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4+ or FOXP3+ T cells on human breast cancer prognosis9,10 and suggest that the targeting of RANKL–RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.