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 6

Loss of TGFBR3 expression in tumors results in enhanced expression of CCL22 by local mDC populations within the tumor microenvironment.

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Loss of TGFBR3 expression in tumors results in enhanced expression of CC...
(A) Ccl22 qRT-PCR in the indicated tumor and TDLN tissues. 3–5 tumors/group. Representative of 3 independent experiments. (B) Ccl22 qRT-PCR in 4T1-sTGFBR3Tet tumors in the presence and absence of doxycycline. Representative of 2 independent experiments. (C) Ccl22 qRT-PCR in 66CL4-TGFBR3-KD and 66CL4-NTC tumors. Representative of 3 independent experiments. (D) CCL22 IHC of 4T1-NEO and 4T1-TGFBR3 TDLNs. 10 ×40 fields over 3 TDLNs/condition. Representative of 2 independent experiments. (E) Ccl22 qRT-PCR of TGF-β–treated bone marrow–derived DCs. IL-4 served as a positive control. Representative of 2 independent experiments. (F) CCL22 immunoprecipitation and Western blot of TGF-β–treated bone marrow–derived DCs. UT, untreated. Representative of 3 independent experiments. (G) CCL22 ELISA of CM after TGF-β treatment of bone marrow–derived DCs. Performed in duplicate. Representative of 2 independent experiments. Data are mean ± SEM. *P < 0.05, **P < 0.005, 2-tailed Student’s t test.