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

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.

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 8

Translational implications of TGFBR3-dependent regulation of antitumor immunity in breast cancer.

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Translational implications of TGFBR3-dependent regulation of antitumor i...
(A) Oncomine microarray expression analysis of TGFBR3, IDO, CCL22, and FOXP3 in human normal mammary tissues (N) relative to human breast cancers (T). Fold changes in gene expression relative to normal mammary tissues are indicated. See Supplemental Table 2. (B) Loss of TGFBR3 by tumor cells enhances TGF-β–mediated upregulation of IDO and CCL22 by local pDC and mDC populations, respectively, resulting in enhanced Treg activation and recruitment. (C) TGF-β signaling inhibition in combination with HER2/NEU vaccination in a HER2/NEU-expressing 4T1 mammary carcinoma model. AdLacZ was used as control vector. 8 mice/group. Representative of 2 independent experiments. (D) IFN-γ ELISPOT analysis of HER2/NEU-specific T cell responses. PMA/ionomycin served as a positive control; HIV peptide mix served as an irrelevant peptide negative control. 3 mice/group. Representative of 2 independent experiments. **P < 0.005, ***P < 0.0005, 2-tailed Student’s t test.