Lukhele et al. demonstrated that interferon regulatory factor 2 (IRF2) redirects interferon signaling to program CD8+ T cell exhaustion and suppress tumor control. IRF2 is upregulated in tumor-infiltrating CD4+ and CD8+ T cells in humans and mice, particularly in activated and interferon-stimulated gene-producing CD8+ TILs. IRF2-deficient CD8+ T resisted a T cell exhaustion program within the tumor, maintained effector functions, improved tumor control, and increased responsiveness to immune checkpoint and adoptive cell therapies in several tumor models. IRF2-deficient CD8+ T cells required continuous IFN-I and IFN-II signals for long-term tumor control.
Contributed by Shishir Pant
ABSTRACT: Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8(+) T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8(+) T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.
Author Info: (1) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. Electronic address: sabelo.m.lukhele@gmail.com. (2) Princess Margaret Cancer Center, Un
Author Info: (1) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. Electronic address: sabelo.m.lukhele@gmail.com. (2) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (3) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. (4) Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. (5) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (6) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (7) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (8) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (9) Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (10) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (11) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (12) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (13) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (14) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (15) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada. (16) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. (17) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. (18) Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. (19) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. (20) Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada; Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8 Canada. Electronic address: dbrooks@uhnresearch.ca.
