Host STAT2/type I Interferon Axis Controls Tumor Growth

Overview

Journal Int J Cancer

Specialty Oncology

Date 2014 Jun 5

PMID 24895110

Citations 20

Authors

Chanyu Yue

Jun Xu

Marc Daryl Tan Estioko

Kevin P Kotredes

Yolanda Lopez-Otalora

Brendan A Hilliard

Darren P Baker

Stefania Gallucci

Ana M Gamero

Affiliations

Soon will be listed here.

Abstract

The role of STAT2 in mediating the antigrowth effects of type I interferon (IFN) is well-documented in vitro. Yet evidence of IFN-activated STAT2 as having tumor suppressor function in vivo and participation in antitumor immunity is lacking. Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth. Stat2(-/-) mice formed larger tumors compared to wild type (WT) mice. IFN-β treatment of Stat2(-/-) mice did not cause tumor regression. Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2(-/-) mice. Additionally, we found tumor antigen cross-presentation by Stat2(-/-) dendritic cells to T cells to be impaired. Adoptive transfer of tumor antigen specific CD8(+) T cells primed by Stat2(-/-) dendritic cells into tumor-bearing Stat2(-/-) mice did not induce tumor regression with IFN-β intervention. We observed that an increase in the number of CD4(+) and CD8(+) T cells in the draining lymph nodes of IFN-β-treated tumor-bearing WT mice was absent in IFN-β treated Stat2(-/-) mice. Thus our study provides evidence for further evaluation of STAT2 function in cancer patients receiving type I IFN based immunotherapy.

Citing Articles

Interferons in Colorectal Cancer Pathogenesis and Therapy.

Petrova L, Bunz F Dis Res. 2024; 4(1):31-39.

PMID: 38962090 PMC: 11220628. DOI: 10.54457/dr.202401005.

STAT3 drives the malignant progression of low-grade gliomas through modulating the expression of STAT1, FOXO1, and MYC.

Li Y, Jiang F, Zhu S, Jia H, Li C Front Mol Biosci. 2024; 11:1419072.

PMID: 38948079 PMC: 11211654. DOI: 10.3389/fmolb.2024.1419072.

STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs.

Chiriac M, Hracsko Z, Becker C, Neurath M Cancers (Basel). 2023; 15(22).

PMID: 38001683 PMC: 10670206. DOI: 10.3390/cancers15225423.

The duality of STAT2 mediated type I interferon signaling in the tumor microenvironment and chemoresistance.

Canar J, Darling K, Dadey R, Gamero A Cytokine. 2022; 161:156081.

PMID: 36327541 PMC: 9720715. DOI: 10.1016/j.cyto.2022.156081.

Multi-omics analysis for potential inflammation-related genes involved in tumour immune evasion via extended application of epigenetic data.

Huang C, Wang N, Zhang N, Chen Z, Ni Z, Liu X Open Biol. 2022; 12(8):210375.

PMID: 35946310 PMC: 9364145. DOI: 10.1098/rsob.210375.

References

Gamero A, Larner A . Vanadate facilitates interferon alpha-mediated apoptosis that is dependent on the Jak/Stat pathway. J Biol Chem. 2001; 276(17):13547-53. DOI: 10.1074/jbc.M007948200. View

Montoya M, Schiavoni G, Mattei F, Gresser I, Belardelli F, Borrow P . Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood. 2002; 99(9):3263-71. DOI: 10.1182/blood.v99.9.3263. View

Fu X, Schindler C, Improta T, Aebersold R, Darnell Jr J . The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992; 89(16):7840-3. PMC: 49807. DOI: 10.1073/pnas.89.16.7840. View

Clifford J, Walch E, Yang X, Xu X, Alberts D, Clayman G . Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis. Clin Cancer Res. 2002; 8(7):2067-72. View

Lembo M, Sacchi C, Zappador C, Bellomo G, Gaboli M, Pandolfi P . Inhibition of cell proliferation by the interferon-inducible 204 gene, a member of the Ifi 200 cluster. Oncogene. 1998; 16(12):1543-51. DOI: 10.1038/sj.onc.1201677. View

Plumlee C, Lee C, Beg A, Decker T, Shuman H, Schindler C . Interferons direct an effective innate response to Legionella pneumophila infection. J Biol Chem. 2009; 284(44):30058-66. PMC: 2781560. DOI: 10.1074/jbc.M109.018283. View

Overwijk W, Theoret M, Finkelstein S, Surman D, de Jong L, Vyth-Dreese F . Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med. 2003; 198(4):569-80. PMC: 2194177. DOI: 10.1084/jem.20030590. View

Picaud S, Bardot B, De Maeyer E, Seif I . Enhanced tumor development in mice lacking a functional type I interferon receptor. J Interferon Cytokine Res. 2002; 22(4):457-62. DOI: 10.1089/10799900252952244. View

Asselin-Paturel C, Brizard G, Chemin K, Boonstra A, OGarra A, Vicari A . Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J Exp Med. 2005; 201(7):1157-67. PMC: 2213121. DOI: 10.1084/jem.20041930. View

10.

Wang S, Zhang X, Ju Y, Zhao B, Yan X, Hu J . MicroRNA-146a feedback suppresses T cell immune function by targeting Stat1 in patients with chronic hepatitis B. J Immunol. 2013; 191(1):293-301. DOI: 10.4049/jimmunol.1202100. View

11.

Swann J, Hayakawa Y, Zerafa N, Sheehan K, Scott B, Schreiber R . Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J Immunol. 2007; 178(12):7540-9. DOI: 10.4049/jimmunol.178.12.7540. View

12.

Roychowdhury S, May Jr K, Tzou K, Lin T, Bhatt D, Freud A . Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2. Cancer Res. 2004; 64(21):8062-7. DOI: 10.1158/0008-5472.CAN-04-1860. View

13.

Chen L, Wei P, Liu T, Kao C, Pai L, Lee C . STAT2 hypomorphic mutant mice display impaired dendritic cell development and antiviral response. J Biomed Sci. 2009; 16:22. PMC: 2653529. DOI: 10.1186/1423-0127-16-22. View

14.

Petro M, Kish D, Guryanova O, Ilyinskaya G, Kondratova A, Fairchild R . Cutaneous tumors cease CXCL9/Mig production as a result of IFN-γ-mediated immunoediting. J Immunol. 2012; 190(2):832-41. DOI: 10.4049/jimmunol.1201906. View

15.

Stark G, Kerr I, Williams B, Silverman R, Schreiber R . How cells respond to interferons. Annu Rev Biochem. 1998; 67:227-64. DOI: 10.1146/annurev.biochem.67.1.227. View

16.

Sriram U, Biswas C, Behrens E, Dinnall J, Shivers D, Monestier M . IL-4 suppresses dendritic cell response to type I interferons. J Immunol. 2007; 179(10):6446-55. DOI: 10.4049/jimmunol.179.10.6446. View

17.

Takemoto Y, Yano H, Momosaki S, Ogasawara S, Nishida N, Kojiro S . Antiproliferative effects of interferon-alphaCon1 on ovarian clear cell adenocarcinoma in vitro and in vivo. Clin Cancer Res. 2004; 10(21):7418-26. DOI: 10.1158/1078-0432.CCR-04-0279. View

18.

Schindler C, Shuai K, Prezioso V, Darnell Jr J . Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992; 257(5071):809-13. DOI: 10.1126/science.1496401. View

19.

Padovan E, Spagnoli G, Ferrantini M, Heberer M . IFN-alpha2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8+ effector T cells. J Leukoc Biol. 2002; 71(4):669-76. View

20.

Diamond M, Kinder M, Matsushita H, Mashayekhi M, Dunn G, Archambault J . Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 2011; 208(10):1989-2003. PMC: 3182061. DOI: 10.1084/jem.20101158. View