The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

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 demonstrate...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Vol. 55; no. 12; pp. 2369 - 2385.e10
Main Authors:	Lukhele, Sabelo, Rabbo, Diala Abd, Guo, Mengdi, Shen, Jian, Elsaesser, Heidi J., Quevedo, Rene, Carew, Madeleine, Gadalla, Ramy, Snell, Laura M., Mahesh, Lawanya, Ciudad, M. Teresa, Snow, Bryan E., You-Ten, Annick, Haight, Jillian, Wakeham, Andrew, Ohashi, Pamela S., Mak, Tak W., Cui, Weiguo, McGaha, Tracy L., Brooks, David G.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 13-12-2022
Subjects:	adoptive cell transfer cancer CD8+ T cells CD8-Positive T-Lymphocytes CyTOF Humans immunotherapy interferon gamma interferon regulatory factor 2 Interferon Regulatory Factor-2 - genetics Interferon Type I IRF2 Neoplasms - pathology T cell exhaustion Transcription Factors type I interferon type I interferon CD8+ T cells interferon gamma interferon regulatory factor 2 IRF2 immunotherapy T cell exhaustion cancer CyTOF adoptive cell transfer CD8(+) T cells
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Summary:	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. [Display omitted] •IRF2 expression by CD8+ TILs drives T cell exhaustion•IRF2 drives the suppressive program induced by interferons•IRF2 deletion enables CD8+ T cell-driven control of multiple tumor types•IRF2 deficiency boosts efficacy of adoptive cell and immune checkpoint therapies How interferons switch from pro-inflammatory to immunosuppressive programs that facilitate cancer growth has remained enigmatic. Lukhele et al. establish that the transcription factor interferon regulatory factor 2 attenuates and redirects interferon signaling to program CD8+ T cell exhaustion to avert tumor control.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 SL and DGB designed the research. SL, MG, JS, HJE, MC, LM and MTC performed experiments. BES, AYT, JH, AW, TWM, TLM, PSO provided reagents. SL, DAR, RQ and DGB analyzed data. RG, LMS, PSO, WC., TLM provided intellectual, technical input and discussion. SL and DGB wrote the manuscript. Author Contributions
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2022.10.020