Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment
Hridesh Banerjee,
Hector Nieves-Rosado,
Aditi Kulkarni,
Benjamin Murter,
Kyle V. McGrath,
Uma R. Chandran,
Alexander Chang,
Andrea L. Szymczak-Workman,
Lazar Vujanovic,
Greg M. Delgoffe,
Robert L. Ferris,
Lawrence P. Kane
Affiliations
Hridesh Banerjee
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Hector Nieves-Rosado
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Graduate Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Aditi Kulkarni
Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Benjamin Murter
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Graduate Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Kyle V. McGrath
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Uma R. Chandran
Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Alexander Chang
Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Andrea L. Szymczak-Workman
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Lazar Vujanovic
Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Greg M. Delgoffe
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Robert L. Ferris
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Lawrence P. Kane
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Corresponding author
Summary: Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, this protein is expressed by a much larger proportion of tumor-infiltrating Treg cells. Using a mouse model that drives cell-type-specific inducible Tim-3 expression, we show that expression of Tim-3 by Treg cells is sufficient to drive Treg cells to a more effector-like phenotype, resulting in increases in suppressive activity, effector T cell exhaustion, and tumor growth. We also show that T-reg-cell-specific inducible deletion of Tim-3 enhances anti-tumor immunity. Enhancement of Treg cell function by Tim-3 is strongly correlated with increased expression of interleukin-10 (IL-10) and a shift to a more glycolytic metabolic phenotype. Our data demonstrate that Tim-3+ Treg cells may be a relevant therapeutic target cell type for the treatment of cancer.