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 5

Tumor-derived sTGFBR3 inhibits expression and enzymatic activity of IDO by local pDC populations within the tumor microenvironment.

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Tumor-derived sTGFBR3 inhibits expression and enzymatic activity of IDO ...
(A) Ido qRT-PCR analysis of 4T1-NEO and 4T1-TGFBR3 tumors and TDLNs. (B) IDO immunofluorescence of TDLNs. Representative ×20 images are also shown. (C) TDLN pDC Ido qRT-PCR. Pooled from 3 independent experiments. (D) TDLN pDC IDO immunofluorescence. Representative ×100 images of pDCs isolated in 2 independent experiments are also shown. Isotype controls showed no staining. (E) Ido qRT-PCR analysis of 4T1-NEO and 4T1-TGFBR3 TDLNs after 2G7 treatment. 6 mice/group. (F) In-cell Western blot (left; pooled from 3 independent experiments) and traditional Western blot (right; representative of 2 independent experiments) of pDC IDO expression in the presence or absence of 4T1-NEO or 4T1-TGFBR3 CM. IFN-γ served as a positive control. (G) pDC-derived IDO enzymatic activity, measured after coincubation with 4T1-NEO or 4T1-TGFBR3 CM. sTGFBR3 served as a positive control. Pooled from 3 independent experiments. (H) Whole 4T1-sTGFBR3Tet TDLN IDO enzymatic assay with or without doxycycline. (I) 4T1-NEO and 4T1-TGFBR3 TDLN-derived pDC mixed lymphocyte proliferation assay. Representative of 2 independent assays. Data are mean ± SEM. *P < 0.05, **P < 0.005, 2-tailed Student’s t test.