TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer.
Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFβ1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo The PD-1hisubset seen in CD8+TILs is absent in Smad3-deficient tumor-specific CD8+TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity. In addition to TGFβ1's previously known effects on T-cell function, our findings suggest that TGFβ1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFβ-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit antitumor immunity.



Engagement of the coinhibitory receptor PD-1 or its ligand, PD-L1, dramatically inhibits the antitumor function of TILs within the TME. Our findings represent a novel immunosuppressive function of TGFβ and demonstrate that TGFβ1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs. Cancer Discov; 6(12); 1366-81. ©2016 AACRThis article is highlighted in the In This Issue feature, p. 1293.
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Benjamin V
BV
Park
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Zachary T
ZT
Freeman
Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Ali
A
Ghasemzadeh
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Michael A
MA
Chattergoon
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Alleluiah
A
Rutebemberwa
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jordana
J
Steigner
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Matthew E
ME
Winter
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Thanh V
TV
Huynh
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Suzanne M
SM
Sebald
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Se-Jin
SJ
Lee
Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Fan
F
Pan
Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Drew M
DM
Pardoll
Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland. acox@jhmi.edu.|Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Andrea L
AL
Cox
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019169:Jurkat Cells; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D059016:Tumor Microenvironment
D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
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