Wertheimer et al. showed that TAMs were the primary source of IL-23 in tumors, and highly activated Foxp3+ Treg cells comprised a large portion of the IL-23R+ T cells in the TME of solid tumor-bearing mice. Il-23r ablation in only Foxp3+ Treg cells led to reduced tumor growth and, in the TME, to increases of TEFF cells and phenotypically less suppressive myeloid and Treg cells, and to the reduction of Il23r-KO CD44+CD62L- effector (e)Treg cells. Under inflammatory conditions in vitro, IL-23 stabilized Foxp3 expression by Treg cells and induced their differentiation to an eTreg cell suppressive state. IL23Rhigh Treg cells in human tumors had higher expression of the eTreg cell suppressive gene profile.
Contributed by Paula Hochman
ABSTRACT: Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (T(reg)) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in T(reg) cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector T(reg) cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity.
Author Info: (1) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (2) Department of Inflammation Research, Institute of Expe
Author Info: (1) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (2) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (3) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (4) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (5) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (6) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Department of Pharmacology, Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. (7) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (8) Department of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany. (9) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (10) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (11) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (12) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (13) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (14) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (15) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (16) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (17) Institute for Experimental Neuroimmunology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. (18) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (19) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (20) Department of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany. Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany. (21) Department of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany. Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany. (22) Department of Immunology, University of Washington, Seattle, WA, USA. (23) Institute for Experimental Neuroimmunology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. (24) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. tugues@immunology.uzh.ch. (25) Department of Inflammation Research, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. becher@immunology.uzh.ch.
