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Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment
Brent A. Hanks, … , H. Kim Lyerly, Gerard C. Blobe
Brent A. Hanks, … , H. Kim Lyerly, Gerard C. Blobe
Published August 8, 2013
Citation Information: J Clin Invest. ;123(9):3925-3940. https://doi.org/10.1172/JCI65745.
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Research Article Article has an altmetric score of 28

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment

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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.

Authors

Brent A. Hanks, Alisha Holtzhausen, Katherine S. Evans, Rebekah Jamieson, Petra Gimpel, Olivia M. Campbell, Melissa Hector-Greene, Lihong Sun, Alok Tewari, Amanda George, Mark Starr, Andrew B. Nixon, Christi Augustine, Georgia Beasley, Douglas S. Tyler, Takayu Osada, Michael A. Morse, Leona Ling, H. Kim Lyerly, Gerard C. Blobe

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Figure 1

Loss of TGFBR3 expression promotes tumor progression only in immunocompetent hosts.

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Loss of TGFBR3 expression promotes tumor progression only in immunocompe...
(A) In vivo growth of 4T1-NEO and 4T1-TGFBR3 primary tumors in NSG and WT hosts. 15 mice/group. Red, 4T1-NEO WT; blue, 4T1-TGFBR3 WT; green, 4T1-NEO NSG; purple, 4T1-TGFBR3 NSG. (B) 4T1-NEO/4T1-TGFBR3 tumor burden ratios, based on in vivo bioluminescence monitoring. Representative images are also shown. (C) 4T1-NEO-HER2 and 4T1-TGFBR3-HER2 tumor incidence and volume in NSG and WT hosts. 6 mice/group. Representative of 3 individual experiments. (D) CD3 IHC of 4T1-NEO-HER2 and 4T1-TGFBR3-HER2 tumors. 10 random ×40 fields/condition (representative ×40 images are also shown). Representative of 2 independent experiments. (E) TUNEL analysis of 4T1-NEO-HER2 and 4T1-TGFBR3-HER2 tumors resected from WT and NSG hosts. 10 random ×40 fields/condition. Representative of 2 independent experiments. (F) Annexin-V/PI flow cytometry analysis of resected 4T1-NEO-HER2 and 4T1-TGFBR3-HER2 tumors from WT hosts. Data are mean ± SEM. *P < 0.05, **P < 0.005, 2-tailed Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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