Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.
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.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27708, USA.
Brent A
BA
Hanks
Alisha
A
Holtzhausen
Katherine S
KS
Evans
Rebekah
R
Jamieson
Petra
P
Gimpel
Olivia M
OM
Campbell
Melissa
M
Hector-Greene
Lihong
L
Sun
Alok
A
Tewari
Amanda
A
George
Mark
M
Starr
Andrew B
AB
Nixon
Christi
C
Augustine
Georgia
G
Beasley
Douglas S
DS
Tyler
Takayu
T
Osada
Michael A
MA
Morse
Leona
L
Ling
H Kim
HK
Lyerly
Gerard C
GC
Blobe
D000818:Animals; D045744:Cell Line, Tumor; D054422:Chemokine CCL22 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000276:immunology*
C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C071736:betaglycan