Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.
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Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.
Cell Line, Tumor
Mammary Neoplasms, Experimental
Mice, Inbred BALB C
Mice, Inbred C57BL
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
Published Version (Please cite this version)10.1172/JCI65745
Publication InfoHanks, Brent A; Holtzhausen, Alisha; Evans, Katherine S; Jamieson, Rebekah; Gimpel, Petra; Campbell, Olivia M; ... Blobe, Gerard C (2013). Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest, 123(9). pp. 3925-3940. 10.1172/JCI65745. Retrieved from https://hdl.handle.net/10161/13297.
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Georgia Marie Beasley
Associate Professor of Surgery
Dr. Beasley is an associate professor of surgery in the division of Surgical Oncology at Duke University with a secondary appointment as associate professor in the department of medicine. After playing 3 years in the women’s NBA, she began medical school. She obtained her MD (2008) and Masters of Health Science in clinical research (2010) from Duke University School of Medicine. She then completed general surgical residency at Duke University in 2015, during which time she w
Gerard Conrad Blobe
Professor of Medicine
Our laboratory focuses on transforming growth factor-ß (TGF-ß) superfamily signal transduction pathways, and specifically, the role of these pathways in cancer biology. The TGF-ß superfamily is comprised of a number of polypeptide growth factors, including TGF-βs, bone morphogenetic proteins (BMPs) and activin) that regulate growth, differentiation and morphogenesis in a cell and context specific manner. TGF-ß and the TGF-ß signaling pathway have a dichotomo
Brent A. Hanks
Associate Professor of Medicine
We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of immunotherapies while also developing predictive biomarkers
Herbert Kim Lyerly
George Barth Geller Distinguished Professor of Immunology
Michael Aaron Morse
Professor of Medicine
We are studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on ado
Andrew Benjamin Nixon
Professor in Medicine
Andrew Nixon, PhD, MBA (Professor of Medicine) is Director of the Phase I Biomarker Laboratory, which brings together clinical, translational and basic research to pursue the development of novel biomarkers defining mechanisms of sensitivity, resistance, and toxicity to given therapeutic drug classes, particularly anti-angiogenic agents. Additionally, the laboratory has been appointed as a Molecular Reference Laboratory for the Alliance oncology cooperative group, a national clinical trial resea
Adjunct Associate Professor in the Department of Surgery
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