The Transcription Factor IRF2 Drives Interferon-mediated CD8 T cell Exhaustion to Restrict Anti-tumor Immunity

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2022 Nov 12

PMID 36370712

Authors

Sabelo Lukhele

Diala Abd Rabbo

Mengdi Guo

Jian Shen

Heidi J Elsaesser

Rene Quevedo

Madeleine Carew

Ramy Gadalla

Laura M Snell

Lawanya Mahesh

M Teresa Ciudad

Bryan E Snow

Annick You-Ten

Jillian Haight

Andrew Wakeham

Pamela S Ohashi

Tak W Mak

Weiguo Cui

Tracy L McGaha

David G Brooks

Affiliations

Soon will be listed here.

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.

Citing Articles

The m6A revolution: transforming tumor immunity and enhancing immunotherapy outcomes.

Shi T, Zhang H, Chen Y Cell Biosci. 2025; 15(1):27.

PMID: 39987091 PMC: 11846233. DOI: 10.1186/s13578-025-01368-z.

Eliminating VEGFA+ tumor-associated neutrophils by antibody-drug conjugates boosts antitumor immunity and potentiates PD-1 immunotherapy in preclinical models of cervical cancer.

Yao S, Sun L, Lu Y, Zhu X, Xu R, Yang T Cell Death Dis. 2025; 16(1):115.

PMID: 39971940 PMC: 11840153. DOI: 10.1038/s41419-025-07402-9.

CD226 identifies effector CD8 T cells during tuberculosis and costimulates recognition of -infected macrophages.

Shinkawa T, Chang E, Rakib T, Cavallo K, Lai R, Behar S bioRxiv. 2025; .

PMID: 39896604 PMC: 11785225. DOI: 10.1101/2025.01.22.634303.

Transcriptional signature of CD56 NK cells predicts favourable prognosis in bladder cancer.

Khan M, Sedgwick A, Sun Y, Vivian J, Corbett A, Dolcetti R Front Immunol. 2025; 15:1474652.

PMID: 39877370 PMC: 11772185. DOI: 10.3389/fimmu.2024.1474652.

IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy.

Jiang H, Limsuwannarot S, Kulhanek K, Pal A, Rysavy L, Su L bioRxiv. 2025; .

PMID: 39868284 PMC: 11760723. DOI: 10.1101/2025.01.15.633105.

References

Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco S, Calderon-Copete S, Pais Ferreira D . Intratumoral Tcf1PD-1CD8 T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity. 2019; 50(1):195-211.e10. DOI: 10.1016/j.immuni.2018.12.021. View

Yi Y, Wu H, Gao Q, He H, Li Y, Cai X . Interferon regulatory factor (IRF)-1 and IRF-2 are associated with prognosis and tumor invasion in HCC. Ann Surg Oncol. 2012; 20(1):267-76. DOI: 10.1245/s10434-012-2487-z. View

Utzschneider D, Charmoy M, Chennupati V, Pousse L, Pais Ferreira D, Calderon-Copete S . T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity. 2016; 45(2):415-27. DOI: 10.1016/j.immuni.2016.07.021. View

Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov J, Tamayo P . The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2016; 1(6):417-425. PMC: 4707969. DOI: 10.1016/j.cels.2015.12.004. View

Kaya-Okur H, Wu S, Codomo C, Pledger E, Bryson T, Henikoff J . CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat Commun. 2019; 10(1):1930. PMC: 6488672. DOI: 10.1038/s41467-019-09982-5. View

Harada H, Fujita T, Miyamoto M, Kimura Y, Maruyama M, Furia A . Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell. 1989; 58(4):729-39. DOI: 10.1016/0092-8674(89)90107-4. View

Sakai T, Mashima H, Yamada Y, Goto T, Sato W, Dohmen T . The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer. Pancreas. 2014; 43(6):909-16. DOI: 10.1097/MPA.0000000000000116. View

Scott A, Dundar F, Zumbo P, Chandran S, Klebanoff C, Shakiba M . TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019; 571(7764):270-274. PMC: 7698992. DOI: 10.1038/s41586-019-1324-y. View

Lou X, Sun S, Chen W, Zhou Y, Huang Y, Liu X . Negative feedback regulation of NF-κB action by CITED2 in the nucleus. J Immunol. 2010; 186(1):539-48. DOI: 10.4049/jimmunol.1001650. View

10.

Wherry E . T cell exhaustion. Nat Immunol. 2011; 12(6):492-9. DOI: 10.1038/ni.2035. View

11.

Chen J, Lopez-Moyado I, Seo H, Lio C, Hempleman L, Sekiya T . NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019; 567(7749):530-534. PMC: 6546093. DOI: 10.1038/s41586-019-0985-x. View

12.

Shin H, Blackburn S, Intlekofer A, Kao C, Angelosanto J, Reiner S . A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009; 31(2):309-20. PMC: 2747257. DOI: 10.1016/j.immuni.2009.06.019. View

13.

Sharf R, Azriel A, Lejbkowicz F, Winograd S, Ehrlich R, Levi B . Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. J Biol Chem. 1995; 270(22):13063-9. DOI: 10.1074/jbc.270.22.13063. View

14.

Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang Y . TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 T cell exhaustion. Proc Natl Acad Sci U S A. 2019; 116(25):12410-12415. PMC: 6589758. DOI: 10.1073/pnas.1905675116. View

15.

Snell L, McGaha T, Brooks D . Type I Interferon in Chronic Virus Infection and Cancer. Trends Immunol. 2017; 38(8):542-557. PMC: 8059441. DOI: 10.1016/j.it.2017.05.005. View

16.

Drew P, Franzoso G, Carlson L, Biddison W, Siebenlist U, Ozato K . Interferon regulatory factor-2 physically interacts with NF-kappa B in vitro and inhibits NF-kappa B induction of major histocompatibility class I and beta 2-microglobulin gene expression in transfected human neuroblastoma cells. J Neuroimmunol. 1995; 63(2):157-62. DOI: 10.1016/0165-5728(95)00140-9. View

17.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

18.

Mognol G, Spreafico R, Wong V, Scott-Browne J, Togher S, Hoffmann A . Exhaustion-associated regulatory regions in CD8 tumor-infiltrating T cells. Proc Natl Acad Sci U S A. 2017; 114(13):E2776-E2785. PMC: 5380094. DOI: 10.1073/pnas.1620498114. View

19.

McLane L, Abdel-Hakeem M, Wherry E . CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol. 2019; 37:457-495. DOI: 10.1146/annurev-immunol-041015-055318. View

20.

Rouyez M, Lestingi M, Charon M, Fichelson S, Buzyn A, Dusanter-Fourt I . IFN regulatory factor-2 cooperates with STAT1 to regulate transporter associated with antigen processing-1 promoter activity. J Immunol. 2005; 174(7):3948-58. DOI: 10.4049/jimmunol.174.7.3948. View