title: Interleukin-35 Limits Anti-Tumor Immunity.
abstract: Regulatory T (Treg) cells pose a major barrier to effective anti-tumor immunity. Although Treg cell depletion enhances tumor rejection, the ensuing autoimmune sequelae limits its utility in the clinic and highlights the need for limiting Treg cell activity within the tumor microenvironment. Interleukin-35 (IL-35) is a Treg cell-secreted cytokine that inhibits T cell proliferation and function. Using an IL-35 reporter mouse, we observed substantial enrichment of IL-35(+) Treg cells in tumors. Neutralization with an IL-35-specific antibody or Treg cell-restricted deletion of IL-35 production limited tumor growth in multiple murine models of human cancer. Limiting intratumoral IL-35 enhanced T cell proliferation, effector function, antigen-specific responses, and long-term T cell memory. Treg cell-derived IL-35 promoted the expression of multiple inhibitory receptors (PD1, TIM3, LAG3), thereby facilitating intratumoral T cell exhaustion. These findings reveal previously unappreciated roles for IL-35 in limiting anti-tumor immunity and contributing to T cell dysfunction in the tumor microenvironment.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Turnis
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Deepali V
authors.initials: DV
authors.lastname: Sawant
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Szymczak-Workman
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Andrews
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Beres
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. Electronic address: dvignali@pitt.edu.
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007156:Immunologic Memory; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D059016:Tumor Microenvironment; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007378:Interleukins; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; C569375:interleukin-35, mouse; D000093322:Lymphocyte Activation Gene 3 Protein