Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer

GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Her...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2016-12, Vol.76 (24), p.7106-7117
Main Authors: Metelli, Alessandra, Wu, Bill X, Fugle, Caroline W, Rachidi, Saleh, Sun, Shaoli, Zhang, Yongliang, Wu, Jennifer, Tomlinson, Stephen, Howe, Philip H, Yang, Yi, Garrett-Mayer, Elizabeth, Liu, Bei, Li, Zihai
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Breast Neoplasms - pathology
Carcinogenesis
Female
Heterografts
Humans
Immunohistochemistry
Immunoprecipitation
Membrane Proteins - metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Polymerase Chain Reaction
Tissue Array Analysis
Transforming Growth Factor beta - metabolism
Tumor Escape - physiology
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Summary:GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Here, we report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice. In breast carcinoma-bearing mice that were immunocompetent, GARP overexpression promoted Foxp3 Treg activity, which in turn contributed to enhancing cancer progression and metastasis. Notably, administration of a GARP-specific mAb limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP-TGFβ axis in the tumor microenvironment and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes. Cancer Res; 76(24); 7106-17. ©2016 AACR.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-16-1456