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

Publication ,  Journal Article
Hanks, BA; Holtzhausen, A; Evans, KS; Jamieson, R; Gimpel, P; Campbell, OM; Hector-Greene, M; Sun, L; Tewari, A; George, A; Starr, M; Osada, T ...
Published in: J Clin Invest
September 2013

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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

September 2013

Volume

123

Issue

9

Start / End Page

3925 / 3940

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Tumor Escape
  • Transforming Growth Factor beta
  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Neoplasm Transplantation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hanks, B. A., Holtzhausen, A., Evans, K. S., Jamieson, R., Gimpel, P., Campbell, O. M., … Blobe, G. C. (2013). Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest, 123(9), 3925–3940. https://doi.org/10.1172/JCI65745
Hanks, Brent A., Alisha Holtzhausen, Katherine S. Evans, Rebekah Jamieson, Petra Gimpel, Olivia M. Campbell, Melissa Hector-Greene, et al. “Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.J Clin Invest 123, no. 9 (September 2013): 3925–40. https://doi.org/10.1172/JCI65745.
Hanks BA, Holtzhausen A, Evans KS, Jamieson R, Gimpel P, Campbell OM, et al. Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest. 2013 Sep;123(9):3925–40.
Hanks, Brent A., et al. “Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.J Clin Invest, vol. 123, no. 9, Sept. 2013, pp. 3925–40. Pubmed, doi:10.1172/JCI65745.
Hanks BA, Holtzhausen A, Evans KS, Jamieson R, Gimpel P, Campbell OM, Hector-Greene M, Sun L, Tewari A, George A, Starr M, Nixon AB, Augustine C, Beasley G, Tyler DS, Osada T, Morse MA, Ling L, Lyerly HK, Blobe GC. Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest. 2013 Sep;123(9):3925–3940.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

September 2013

Volume

123

Issue

9

Start / End Page

3925 / 3940

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Tumor Escape
  • Transforming Growth Factor beta
  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Neoplasm Transplantation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice