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 7

TGF-β–mediated suppression of DC function is critical for melanoma tumorigenesis.

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TGF-β–mediated suppression of DC function is critical for melanoma tumor...
(A) SMAD2 and CCL22 Western blot analysis of TGF-β–treated bone marrow–derived DCs isolated from WT and Cd11cdnTGFBR2 mice. IL-4 served as a positive control. t-, total. (B) pSMAD2 and IDO Western blot of TGF-β–treated (T; 20 pM) and untreated (U) splenic PDCA-1+ pDCs, splenic CD11c+PDCA-1– DCs, and CD8+ T cells isolated from WT and Cd11cdnTGFBR2 mice. Representative of 2 independent experiments. (C) B16-mOVA tumor volume in WT and Cd11cdnTGFBR2 mice. 8–9 mice/group. Representative of 2 independent experiments. (D) Myc and Ido qRT-PCR of TDLN pDCs isolated from WT and Cd11cdnTGFBR2 mice. 3 mice/group. Pooled from 2 independent experiments. (E) Foxp3 and Cd8 qRT-PCR of B16-mOVA tumors resected from WT and Cd11cdnTGFBR2 mice. 4 tumors/group. Representative of 2 independent experiments. (F) CD8 and FOXP3 IHC of B16-mOVA tumors resected from WT and Cd11cdnTGFBR2 mice. 20 random ×40 fields/group (representative ×40 images are also shown). Representative of 2 independent experiments. (G) Kb-OVA257–264–specific CD8+ T cell tetramer analysis of splenocytes in B16-mOVA tumor-bearing WT and Cd11cdnTGFBR2 mice. 5 mice/group. Data are mean ± SEM. *P < 0.05, **P < 0.005, 1-way ANOVA (C), 2-tailed Student’s t test (D–G).