Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity
Prabhat K. Purbey,
Joowon Seo,
Manash K. Paul,
Keisuke S. Iwamoto,
Allison E. Daly,
An-Chieh Feng,
Ameya S. Champhekar,
Justin Langerman,
Katie M. Campbell,
Dörthe Schaue,
William H. McBride,
Steven M. Dubinett,
Antoni Ribas,
Stephen T. Smale,
Philip O. Scumpia
Affiliations
Prabhat K. Purbey
Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Corresponding author
Joowon Seo
Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Manash K. Paul
Department of Medicine, Division of Pulmonology and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
Keisuke S. Iwamoto
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Allison E. Daly
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
An-Chieh Feng
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Ameya S. Champhekar
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Justin Langerman
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Katie M. Campbell
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Dörthe Schaue
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
William H. McBride
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Steven M. Dubinett
Department of Medicine, Division of Pulmonology and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Antoni Ribas
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Stephen T. Smale
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Philip O. Scumpia
Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; Corresponding author
Summary: Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1−/− tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.
