TY - JOUR
T1 - Surface expression of TGFβ docking receptor GARP promotes oncogenesis and immune tolerance in breast cancer
AU - Metelli, Alessandra
AU - Wu, Bill X.
AU - Fugle, Caroline W.
AU - Rachidi, Saleh
AU - Sun, Shaoli
AU - Zhang, Yongliang
AU - Wu, Jennifer
AU - Tomlinson, Stephen
AU - Howe, Philip H.
AU - Yang, Yi
AU - Garrett-Mayer, Elizabeth
AU - Liu, Bei
AU - Li, Zihai
N1 - Funding Information:
We thank Drs. Feng Hong, Ephraim Ansa-Addo, Eric Meissner, and Jordan Morreall for critical reading of the manuscript, MUSC Center for Biomedical Imaging and Pathology Core Facilities for technical assistance. This work was supported in part by NIH grants P01CA186866, R01CA188419, R01AI070603, and P30CA138313 (Z. Li), TL1 TR001451 and UL1 TR001450 (C.W. Fugle), as well as P30 CA138313 (Z. Li., P. Howe, and E. Garrett-Mayer). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/12/15
Y1 - 2016/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-1456
DO - 10.1158/0008-5472.CAN-16-1456
M3 - Article
C2 - 27913437
AN - SCOPUS:85006870995
VL - 76
SP - 7106
EP - 7117
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 24
ER -
