title: Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression.
abstract: Tumor-reactive T cells become unresponsive in advanced tumors. Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8⁺ T cells from proliferating and upregulating Granzyme-B and interferon-γ in response to tumor antigens. Accordingly, Foxp1-deficient lymphocytes induced rejection of incurable tumors and promoted protection against tumor rechallenge. Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8⁺ T cells in response to microenvironmental transforming growth factor-β (TGF-β), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-β-induced c-Jun transcriptional repression, which abrogated T cell activity. Our results unveil a fundamental mechanism of T cell unresponsiveness different from anergy or exhaustion, driven by TGF-β signaling on tumor-associated lymphocytes undergoing Foxp1-dependent transcriptional regulation.
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tesone
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Svoronos
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Fahmida
authors.initials: F
authors.lastname: Sarmin
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Borowsky
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA; Rena Rowan Breast Center, University of Pennsylvania, Philadelphia, PA 19104-1693, USA; Abramson Cancer Center Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D053804:Granzymes / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051899:Smad2 Protein / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D053804:Granzymes