Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.
Abstract
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.
Type
Journal articleSubject
AnimalsCell Line, Tumor
Chemokine CCL22
Dendritic Cells
Down-Regulation
Female
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Mammary Neoplasms, Experimental
Melanoma, Experimental
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Transplantation
Proteoglycans
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
Tumor Escape
Tumor Microenvironment
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https://hdl.handle.net/10161/13297Published Version (Please cite this version)
10.1172/JCI65745Publication Info
Hanks, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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
Takuya Osada
Adjunct Associate Professor in the Department of Surgery
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