You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Kebin Liu
 -- 2433 2022-08-30 13:49:09 |
2 format
Jason Zhu
 Meta information modification 2433 2022-08-31 03:47:46 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Moorman, H.R.;  Reategui, Y.;  Poschel, D.B.;  Liu, K. IRF8. Encyclopedia. Available online: https://encyclopedia.pub/entry/26673 (accessed on 10 July 2025).
Moorman HR,  Reategui Y,  Poschel DB,  Liu K. IRF8. Encyclopedia. Available at: https://encyclopedia.pub/entry/26673. Accessed July 10, 2025.
Moorman, Hannah R., Yazmin Reategui, Dakota B. Poschel, Kebin Liu. "IRF8" Encyclopedia, https://encyclopedia.pub/entry/26673 (accessed July 10, 2025).
Moorman, H.R.,  Reategui, Y.,  Poschel, D.B., & Liu, K. (2022, August 30). IRF8. In Encyclopedia. https://encyclopedia.pub/entry/26673
Moorman, Hannah R., et al. "IRF8." Encyclopedia. Web. 30 August, 2022.
IRF8
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cells11172630

Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of Irf8 leads to massive accumulation of CD11b+Gr1+ immature myeloid cells (IMCs), particularly the CD11b+Ly6Chi/+Ly6G− polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, Irf8 is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b+ Ly6G+Ly6Clo monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases.

IRF8 Function Cancer

1. Introduction

Interferon regulatory factor 8 (IRF8), originally termed interferon consensus sequence binding protein (ICSBP), is a member of the IRF transcription factor [1]. IRFs were first identified as a regulator of the type I interferon (IFN-I) response for the activation of IFN-stimulated genes that are essential for immune response to viruses and other pathogens [2][3][4][5], and are now known to be important in turning pathogen associated molecular patterns into chromatin changes and eventually into immune cell activation [6]. IRF8 was first cloned as an IFNγ-inducible nuclear protein-encoding gene that binds to specific IFN-responsive DNA motif in the major histocompatibility complex class I (MHC I) genes [7]. IRF8 has since been determined to be constitutively expressed and IFNγ inducible and plays key roles in the IFN response pathways in immune cell differentiation and function, as well as in non-hematopoietic cell turnover and pathogenesis [8][9][10][11][12][13][14][15][16][17][18][19][20][21].

2. IRF8 Function and Diseases

A 915C> T mutation (R294C) resembles IRF8 KO mice in accumulating immature myeloid cells (IMCs) and causes susceptibility to infection in mice [22][23]. K108E and T80A mutations results in IRF8 loss of function that leads to impaired dendritic cell monocyte development and function in humans or mice [9][24]. A 331C>T [R111* (stop codon)] mutation may cause IRF8 loss of function, resulting in neutrophilia, monocytopenia and decreased CD3+ T cell and CD8+ T cell counts in humans [25]. IRF-8 polymorphisms have been implicated in the development of autoimmune thyroiditis, Behcet’s disease and, increased susceptibility to tuberculosis (TB). The IRF-8 polymorphism, rs17445836, was associated with both development of autoimmune thyroiditis and TB [26][27][28]. Moreover, IRF8 also functions as an apoptosis regulator in hematopoietic tumor cells [29][30][31][32]. IRF8’s intrinsic function in hematopoietic cells thus plays essential roles in myelopoiesis to regulate immune cell activation and immune suppressors under physiological conditions [20][33][34] and in suppression of tumorigenesis [29][30][31][32]. Indeed, IRF8 has been shown to function as a suppressor of acute myeloid leukemia (AML) [35]. However, IRF8 has recently been reported to function as an acute myeloid leukemia (AML)-specific susceptibility factor and promote AML cell proliferation. High IRF8 expression is associated with poorer prognoses in certain AML patients [36]. On the other hand, IRF8 is also expressed in non-hematopoietic cells [8][10][37][38][39][40][41][42][43][44][45]. IRF8 functions as an apoptosis regulator in several types of human tumor cells [38][41][46][47] and mice with IRF8 deletion only in the colon epithelial cells develop significantly more colon tumors than the littermate control mice [41]. Furthermore, IRF8 expression level is positively linked to cancer patient prognosis and response to immunotherapy [18][19]. IRF8 therefore also functions as a tumor suppressor in non-hematopoietic cells.

3. IRF8 Function as a Transcription Factor That Depends on IAD-Interacting Transcription Factors to Exert Its Activity

Analysis and comparison of the IRF8 protein sequences in the National Center for Biotechnology Information with the Blast protein program [48] revealed that IRF8 proteins are highly conserved in mammals, with an 89.44–89.67% similarity in amino acid sequences between human and mouse IRF8 proteins. Human IRF8 gene is located at chromosome 16 with 23,228 bp that encodes 9 exons and 8 introns. The human IRF8 protein is 426 amino acids long with a DNA-binding domain (DBD) and an IRF association domain (IAD) [23]. The DBD binds to unique consensus sequence motifs at promoters of genes, such as IFN-responsive genes, to regulate transcription. The IAD associates with other transcription factors to direct the IRF8 protein complex binding to specific DNA motif to regulate specific gene transcription. IRF8 has weak DNA-binding affinity and its transcription regulatory activity therefore depends on its IAD association with other transcriptional factors to form a transcription complex which renders IRF8 specific and high affinity to bind to the unique DNA motifs at gene promoters [23][34][49][50]. IRF8 functions as either a transcriptional activator or repressor and it is the IAD-associated transcription factor(s) that dictates IRF8 bindingand transcriptional activity [20][23][33][51][52][53][54][55].
IRF8 transcription factor protein complexes selectively binds to certain types of DNA consensus sequence motifs to activate or repress gene transcription [33][56][57][58][59]. Heterodimers of IRF8 in association with IRFs (e.g., IRF1 or IRF2) bind to the IFN-stimulated response element (ISRE: [(A/G)NGAAANNGAAACT]. IRF8-IRF1/IRF2 heterodimers generally bind to promoter region ISRE to repress the transcription of the downstream genes [1]. The IRF8-Ets (Erythroblast Transformation Specific/E-twenty-six) and IRF8-PU1 heterodimers bind to the Ets-RF8 composite element (EICE: GGAANNGAAA) or the IRF8-Ets composite sequence (IECS: GAAANN(N)GGAA) to activate target gene transcription [52][53][56][57][58][60][61][62][63][64][65][66]. In addition, IRF8 has been shown to form a complex with the JUNB/AP-1-BATF3and/or IRF4 and binds to the AP-1-IRFcomposite elements 1 and 2 [AICE1:TTTCNNNNTGA(G/C)T(C/A)A; AICE2: GAAATGA(G/C)T(C/A)A] to activate transcription of genes [11][67][68][69]. For example, IRF8 forms a heterodimer with AP-1 factor BATF and binds to the AICE site to promote gene activation in T helper 17 (Th17) cells, B and dendritic cells [67][69][70]. It has been shown that IRF8 also forms complexes with IRF4, PU.1 and BATF at the ISRE-like sites to activate Il9 and Il21 transcription in Th9 cells [66]. IRF8 can also form a heterodimer with IRF1 or IRF2 [71] that binds to ISRE element to repress transcription of genes induced by IFN and retinoic acid [72][73] or to activate target gene expression [50][70][71]. Although IRF8 binds to IECS to activate gene expression [1][54], IRF8 binding to IECS element at the Asah1 promoter represses acid ceramidase expression [31]. Furthermore, IRF6 interacts with ETV6 to repress Il4 transcription in Th9 cells [66].

4. IRF8 Expression Profiles

The expression of IRF8 was originally detected in hematopoietic cells and its expression has long been thought to be restricted to hematopoietic cells [56]. Although IRF8 is abundantly expressed in hematopoietic cells, particularly in B cells and DCs, it has since been determined that IRF8 is also expressed in epithelial cells in the intestine, colon, ocular lens, skin, lung, liver, and heart [8][10][37][38][39][40][41][42][43][44][45]. Analysis of IRF8 expression from single cell RNA sequencing datasets revealed that IRF8 is indeed expressed in several types of non-hematopoietic cells, including theca cells, melanocytes, enterocytes and intestinal cells in humans.

5. IRF8 Expression and Function in Non-Hematopoietic Cancer Cells

While much research has been dedicated to understanding the role of IRF8 in hematopoietic cells, less research has investigated the role of IRF8 in non-hematopoietic cells. In certain types of cancers, IRF8 functions as a tumor suppressor gene [18][19][42][43][44], and its expression is regulated by DNA methylation or micro-RNA interference [74]. In breast and lung cancer, IRF8 is downregulated as a result of promoter hypermethylation [43][75][76], and a higher IRF8 expression level was associated with a better prognosis [19]. Similarly, in gastric, nasopharyngeal, esophageal, colorectal, lung, prostate, and renal cell carcinomas the expression of IRF8 is downregulated [43][44][77][78][79][80][81]. IFN-γ induced expression of IRF8 was increased when gastric cancer cells were treated with a demethylating agent [77]. In other cancer cell lines with a methylated IRF8 promoter, IFN-γ treatment showed decreased ability to induce IRF8 expression [78]. Taken together, these studies provide evidence for promoter methylation as a mechanism for IRF8 silencing in certain types of human cancer cells. Analysis of human lung tumor specimens at the single cell level validate the early finding that IRF8 is silenced in the tumor cells. Except for certain tumor-infiltrating immune cells, including certain B cells, pDC and myeloid cells, IRF8 is down-regulated in most cell types and is undetectable in human lung cancer cells [82].
Within non-hematopoietic cancer cells, IRF8 plays a protective role against the formation of a metastatic phenotype. In human colon cancer cells, IRF8 protein levels are inversely correlated with the metastatic phenotype [46][47]. IRF8 expression sensitized the metastatic tumor cells to Fas-mediated apoptosis, indicating that loss of IRF8 in cancers could promote earlier metastasis [46]. It has been suggested that colon cancer cells silence IRF8 expression through inhibition of pSTAT1 function at the IRF8 promoter [47]. IRF8 may also function in non-hematopoietic cancers to negatively regulate the expression of MMP3, a matrix metalloproteinase associated with a poor prognosis and metastasis in various solid organ cancers [83][84][85]. In a chemically-induced sarcoma model, an inverse relationship between IRF8 and MMP3 expression was demonstrated; in a mouse model of mammary cancer, loss of MMP3 reduced spontaneous lung metastasis [86]. This suggests that IRF8 may negatively regulate MMP3 expression, protecting against MMP3-induced metastasis in solid organ tumors. While most research supports an anti-metastasis role for IRF8 in non-hematopoietic cancers, one study found that IRF8 promoted EMT-like phenomena, cell motility, and invasion in a human osteosarcoma cell line providing evidence for a possible role in the acquisition of a metastatic-like phenotype [87].
IRF8 appears to impede the progression and formation of cancer by increasing the expression of tumor suppressor genes, such as Caspase 1, p21, p27, and PTEN [44][81][88]. Expression of tumor suppressor genes inhibited lens cell carcinoma growth upon transfection with IRF8 [88]. Similarly, IRF8-induced expression of p27 induced lung cancer cell senescence [44]. Mechanistically, IRF8 was shown to inhibit Akt activity thereby inducing the accumulation of p27 and promoting senescence. While IRF8 increases tumor suppressor genes, one study also showed an IRF8-induced decrease in oncogene (Yap1 and Survivin) expression in renal cell carcinoma cell lines [81]. In this cell line, ectopic expression of IRF8 induced cell cycle G2/M arrest and apoptosis further supporting IRF8’s role in impeding cancer progression.
IRF8 functions as a promoter of Fas-mediated apoptosis. This form of extrinsic apoptosis is key to immune clearance of tumor cells and is targeted in cancer therapy [89][90]. Modification of Fas expression can render immune checkpoint inhibitor (ICI) therapies unsuccessful. Colon cancer cells with low Fas expression exhibited decreased sensitivity to FasL-induced apoptosis (a mechanism utilized by ICIs) [91] and lower Fas expression was correlated with decreased survival in colon cancer patients [92]. One mechanism by which cancer cells may alter the expression of Fas, and thereby reduce sensitivity to apoptosis, is through downregulation of IRF8.
As previously mentioned, IRF8 is downregulated in many cancers. Studies revolving around a loss of IRF8 have elucidated ways in which IRF8 helps facilitate Fas-mediated apoptosis and resulting in tumor immune sensitivity. In soft tissue sarcoma cells, IRF8 was found to be a repressor of FLICE-like protein (FLIP) [93]. Silencing of FLIP and ectopic IRF8 expression each increased susceptibility to FasL-induced apoptosis. This suggests that by repressing FLIP, IRF8 promotes Fas-mediated apoptosis susceptibility. Mechanistically, IRF8 disruption diminishes JAK1 expression and inhibits STAT1 phosphorylation to block IFN-γ induced Fas upregulation in sarcoma cells [94]. IRF8 has also been found to regulate pro-apoptotic and anti-apoptotic factors contributing to Fas-mediated apoptosis. In tumor-induced MDSCs, levels of IRF8 are decreased. IRF8-deficient MDSCs showed an increase in anti-apoptotic Bcl-xL and a decrease in pro-apoptotic Bax, providing a mechanism by which IRF8 downregulation can impede the Fas-mediated apoptosis pathway to evade elimination by T lymphocytes [32]. Another mechanism by which IRF8 can promote Fas-mediated apoptosis is through repression of acid ceramidase (A-CDase). A-CDase upregulation has been implicated in certain cancers such as prostate and breast [95][96][97]. IRF8 induced repression of A-CDase resulted in C16 ceramide accumulation and increased apoptosis sensitivity [31]. This suggests that IRF8 downregulation likely contributes to decreased Fas-mediated apoptosis sensitivity through failure to repress A-CDase. In summary, IRF8 promotes Fas-mediated apoptosis through repression of FLIP and A-CDase and by regulating apoptotic factors such as Bcl-xL and Bax [31][32][93].
IRF8 functions as a link between cancer and the immune system. Poor tumoral homing of DCs and T cells was observed in melanoma-bearing IRF8 KO mice [42]. Additionally, the few DCs that were able to infiltrate the tumor were immature and unable to produce T cell-mediated immune responses. Mechanistically, the decreased tumoral immune infiltration observed in IRF8 KO mice is suggested to occur through the aberrant expression of multiple chemokine receptors and ligands [42]. When IRF8 was induced, immune infiltration was reestablished, and the chemokine expression pattern was reversed. Using a microfluidic device, in which melanoma cells and splenocytes were separated by a microchannel, IRF8 KO splenocytes exhibited a marked decrease in the ability to cross the channel to infiltrate the melanoma cells while melanoma cells exhibited marked propensity to invade the channels suggesting existence of an IRF8-regulated communicating soluble factor [98].
OPN has recently emerged as another immune checkpoint that may compensate PD-L1 function to promote colon tumor immune evasion [99]. IRF8 is expressed in human and mouse gastric and colon epithelial cells [38][41] and binds to the ISRE elements at the Spp1 promoter to repress OPN expression [100]. In human colon and pancreatic cancers, IRF8 expression is down-regulated and OPN is up-regulated [99][100][101][102][103]. scRNA-Seq analysis indicates that OPN is abundantly expressed in tumor cells, MDSCs, and ILCs [99]. Furthermore, scRNA-Seq analysis revealed the tumor-promoting role of SPP1+ cells in cancer [104][105]. OPN protein level is highly elevated in the peripheral blood in human cancer patients and OPN expression is up-regulated in several different types of human cancers [106][107][108][109][110][111][112][113][114]. Silenced IRF8 expression in both tumor cells and tumor-induced myeloid cells by DNA methylation and H3K9me3 deposition at the Irf8 promoter are likely major mechanisms underlying OPN elevation in cancer patients and tumor-bearing mice [41][46][47][78][115]. It was observed that IRF8 KO mice exhibited deficient generation of antigen-specific T cells and this deficiency was due to OPN engagement of CD44 to directly suppress T cell activation [100]. Accordingly, OPN blockade increased activation of tumor-specific T cells and suppressed tumor growth in vivo [99]. OPN is highly expressed in human pancreatic tumor cells and may bind to CD44 on tumor cells via autocrine and paracrine manners to promote pancreatic cancer stemness and progression [101][103]. Therefore, in addition to functioning as a repressor of SPP1 in immune cells such as MDSCs and ILCs, IRF8 not only functions as an intrinsic tumor suppressor [41] but also suppresses tumorigenesis and progression through repressing OPN expression in tumor cells [100].

References

  1. Tamura, T.; Yanai, H.; Savitsky, D.; Taniguchi, T. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 2008, 26, 535–584.
  2. Harada, H.; Fujita, T.; Miyamoto, M.; Kimura, Y.; Maruyama, M.; Furia, A.; Miyata, T.; Taniguchi, T. 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, 729–739.
  3. Miyamoto, M.; Fujita, T.; Kimura, Y.; Maruyama, M.; Harada, H.; Sudo, Y.; Miyata, T.; Taniguchi, T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell 1988, 54, 903–913.
  4. Honda, K.; Takaoka, A.; Taniguchi, T. Type I interferon gene induction by the interferon regulatory factor family of transcription factors. Immunity 2006, 25, 349–360.
  5. Das, A.; Chauhan, K.S.; Kumar, H.; Tailor, P. Mutation in Irf8 Gene (Irf8(R294C)) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs. Front. Immunol. 2021, 12, 758190.
  6. Ikushima, H.; Negishi, H.; Taniguchi, T. The IRF family transcription factors at the interface of innate and adaptive immune responses. Cold Spring Harb. Lab. Press 2013, 78, 105–116.
  7. Driggers, P.H.; Ennist, D.L.; Gleason, S.L.; Mak, W.H.; Marks, M.S.; Levi, B.Z.; Flanagan, J.R.; Appella, E.; Ozato, K. An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc. Natl. Acad. Sci. USA 1990, 87, 3743–3747.
  8. Kim, S.H.; Burton, J.; Yu, C.R.; Sun, L.; He, C.; Wang, H.; Morse, H.C., 3rd; Egwuagu, C.E. Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection. J. Immunol. 2015, 195, 1480–1488.
  9. Hambleton, S.; Salem, S.; Bustamante, J.; Bigley, V.; Boisson-Dupuis, S.; Azevedo, J.; Fortin, A.; Haniffa, M.; Ceron-Gutierrez, L.; Bacon, C.M.; et al. IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 2011, 365, 127–138.
  10. Jiang, D.S.; Wei, X.; Zhang, X.F.; Liu, Y.; Zhang, Y.; Chen, K.; Gao, L.; Zhou, H.; Zhu, X.H.; Liu, P.P.; et al. IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling. Nat. Commun. 2014, 5, 3303.
  11. Grajales-Reyes, G.E.; Iwata, A.; Albring, J.; Wu, X.; Tussiwand, R.; Kc, W.; Kretzer, N.M.; Briseno, C.G.; Durai, V.; Bagadia, P.; et al. Batf3 maintains autoactivation of Irf8 for commitment of a CD8alpha(+) conventional DC clonogenic progenitor. Nat. Immunol. 2015, 16, 708–717.
  12. Lanca, T.; Ungerback, J.; Da Silva, C.; Joeris, T.; Ahmadi, F.; Vandamme, J.; Svensson-Frej, M.; Mowat, A.M.; Kotarsky, K.; Sigvardsson, M.; et al. IRF8 deficiency induces the transcriptional, functional, and epigenetic reprogramming of cDC1 into the cDC2 lineage. Immunity 2022, 55, 1431–1447.
  13. Xia, Y.; Inoue, K.; Du, Y.; Baker, S.J.; Premkumar Reddy, E.; Greenblatt, M.B.; Zhao, B. TGFbeta reprograms TNF stimulation of macrophages towards a non-canonical pathway driving inflammatory osteoclastogenesis. Nat. Commun. 2022, 13, 3920.
  14. Liu, T.T.; Kim, S.; Desai, P.; Kim, D.H.; Huang, X.; Ferris, S.T.; Wu, R.; Ou, F.; Egawa, T.; Van Dyken, S.J.; et al. Ablation of cDC2 development by triple mutations within the Zeb2 enhancer. Nature 2022, 607, 142–148.
  15. Ferris, S.T.; Ohara, R.A.; Ou, F.; Wu, R.; Huang, X.; Kim, S.; Chen, J.; Liu, T.T.; Schreiber, R.D.; Murphy, T.L.; et al. cDC1 vaccines drive tumor rejection by direct presentation independently of host cDC1. Cancer Immunol. Res. 2022, 10, 920–931.
  16. Onuora, S. SLE risk variant regulates IRF8 expression. Nat. Rev. Rheumatol. 2022, 18, 306.
  17. Gao, X.; Ge, J.; Zhou, W.; Xu, L.; Geng, D. IL-10 inhibits osteoclast differentiation and osteolysis through MEG3/IRF8 pathway. Cell Signal 2022, 95, 110353.
  18. Wu, H.; Li, Y.; Shi, G.; Du, S.; Wang, X.; Ye, W.; Zhang, Z.; Chu, Y.; Ma, S.; Wang, D.; et al. Hepatic interferon regulatory factor 8 expression suppresses hepatocellular carcinoma progression and enhances the response to anti-programmed cell death protein-1 therapy. Hepatology 2022.
  19. Gatti, G.; Betts, C.; Rocha, D.; Nicola, M.; Grupe, V.; Ditada, C.; Nunez, N.G.; Roselli, E.; Araya, P.; Dutto, J.; et al. High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer. Breast Cancer Res. 2021, 23, 40.
  20. Murakami, K.; Sasaki, H.; Nishiyama, A.; Kurotaki, D.; Kawase, W.; Ban, T.; Nakabayashi, J.; Kanzaki, S.; Sekita, Y.; Nakajima, H.; et al. A RUNX-CBFbeta-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes. Nat. Immunol. 2021, 22, 301–311.
  21. Nutt, S.L.; Chopin, M. Transcriptional Networks Driving Dendritic Cell Differentiation and Function. Immunity 2020, 52, 942–956.
  22. Turcotte, K.; Gauthier, S.; Tuite, A.; Mullick, A.; Malo, D.; Gros, P. A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. J. Exp. Med. 2005, 201, 881–890.
  23. Tailor, P.; Tamura, T.; Morse, H.C., 3rd; Ozato, K. The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse. Blood 2008, 111, 1942–1945.
  24. Salem, S.; Langlais, D.; Lefebvre, F.; Bourque, G.; Bigley, V.; Haniffa, M.; Casanova, J.L.; Burk, D.; Berghuis, A.; Butler, K.M.; et al. Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8K108E mutation. Blood 2014, 124, 1894–1904.
  25. Dang, D.; Liu, Y.; Zhou, Q.; Li, H.; Wang, Y.; Wu, H. Identification of a novel IRF8 homozygous mutation causing neutrophilia, monocytopenia and fatal infection in a female neonate. Infect. Genet. Evol. 2021, 96, 105121.
  26. Lin, J.D.; Wang, Y.H.; Liu, C.H.; Lin, Y.C.; Lin, J.A.; Lin, Y.F.; Tang, K.T.; Cheng, C.W. Association of IRF8 gene polymorphisms with autoimmune thyroid disease. Eur. J. Clin. Investig. 2015, 45, 711–719.
  27. Ding, S.; Jiang, T.; He, J.; Qin, B.; Lin, S.; Li, L. Tagging single nucleotide polymorphisms in the IRF1 and IRF8 genes and tuberculosis susceptibility. PLoS ONE 2012, 7, e42104.
  28. Jiang, Y.; Wang, H.; Yu, H.; Li, L.; Xu, D.; Hou, S.; Kijlstra, A.; Yang, P. Two Genetic Variations in the IRF8 region are associated with Behcet’s disease in Han Chinese. Sci. Rep. 2016, 6, 19651.
  29. Gabriele, L.; Phung, J.; Fukumoto, J.; Segal, D.; Wang, I.M.; Giannakakou, P.; Giese, N.A.; Ozato, K.; Morse, H.C. Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J. Exp. Med. 1999, 190, 411–421.
  30. Burchert, A.; Cai, D.; Hofbauer, L.C.; Samuelsson, M.K.; Slater, E.P.; Duyster, J.; Ritter, M.; Hochhaus, A.; Muller, R.; Eilers, M.; et al. Interferon consensus sequence binding protein (ICSBP.; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2. Blood 2004, 103, 3480–3489.
  31. Hu, X.; Yang, D.; Zimmerman, M.; Liu, F.; Yang, J.; Kannan, S.; Burchert, A.; Szulc, Z.; Bielawska, A.; Ozato, K.; et al. IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia. Cancer Res. 2011, 71, 2882–2891.
  32. Hu, X.; Bardhan, K.; Paschall, A.V.; Yang, D.; Waller, J.L.; Park, M.A.; Nayak-Kapoor, A.; Samuel, T.A.; Abrams, S.I.; Liu, K. Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer. J. Biol. Chem. 2013, 288, 19103–19115.
  33. Tamura, T.; Ozato, K. ICSBP/IRF-8: Its regulatory roles in the development of myeloid cells. J. Interferon Cytokine Res. 2002, 22, 145–152.
  34. Kurotaki, D.; Yamamoto, M.; Nishiyama, A.; Uno, K.; Ban, T.; Ichino, M.; Sasaki, H.; Matsunaga, S.; Yoshinari, M.; Ryo, A.; et al. IRF8 inhibits C/EBPalpha activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat. Commun. 2014, 5, 4978.
  35. Sharma, A.; Yun, H.; Jyotsana, N.; Chaturvedi, A.; Schwarzer, A.; Yung, E.; Lai, C.K.; Kuchenbauer, F.; Argiropoulos, B.; Gorlich, K.; et al. Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling. Leukemia 2015, 29, 157–168.
  36. Liss, F.; Frech, M.; Wang, Y.; Giel, G.; Fischer, S.; Simon, C.; Weber, L.M.; Nist, A.; Stiewe, T.; Neubauer, A.; et al. IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells. Cancers 2021, 13, 764.
  37. Wang, H.; Yan, M.; Sun, J.; Jain, S.; Yoshimi, R.; Abolfath, S.M.; Ozato, K.; Coleman, W.G., Jr.; Ng, A.P.; Metcalf, D.; et al. A Reporter Mouse Reveals Lineage-Specific and Heterogeneous Expression of IRF8 during Lymphoid and Myeloid Cell Differentiation. J. Immunol. 2014, 193, 1766–1777.
  38. Yan, M.; Wang, H.; Sun, J.; Liao, W.; Li, P.; Zhu, Y.; Xu, C.; Joo, J.; Sun, Y.; Abbasi, S.; et al. Cutting Edge: Expression of IRF8 in Gastric Epithelial Cells Confers Protective Innate Immunity against Helicobacter pylori Infection. J. Immunol. 2016, 196, 1999–2003.
  39. Li, W.; Nagineni, C.N.; Ge, H.; Efiok, B.; Chepelinsky, A.B.; Egwuagu, C.E. Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens. J. Biol. Chem. 1999, 274, 9686–9691.
  40. Sun, L.; St Leger, A.J.; Yu, C.R.; He, C.; Mahdi, R.M.; Chan, C.C.; Wang, H.; Morse, H.C., 3rd; Egwuagu, C.E. Interferon Regulator Factor 8 (IRF8) Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells. PLoS ONE 2016, 11, e0155420.
  41. Ibrahim, M.L.; Klement, J.D.; Lu, C.; Redd, P.S.; Xiao, W.; Yang, D.; Browning, D.D.; Savage, N.M.; Buckhaults, P.J.; Morse, H.C., 3rd; et al. Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis. Cell Rep. 2018, 25, 3036–3046.e6.
  42. Mattei, F.; Schiavoni, G.; Sestili, P.; Spadaro, F.; Fragale, A.; Sistigu, A.; Lucarini, V.; Spada, M.; Sanchez, M.; Scala, S.; et al. IRF-8 controls melanoma progression by regulating the cross talk between cancer and immune cells within the tumor microenvironment. Neoplasia 2012, 14, 1223–1235.
  43. Suzuki, M.; Ikeda, K.; Shiraishi, K.; Eguchi, A.; Mori, T.; Yoshimoto, K.; Shibata, H.; Ito, T.; Baba, Y.; Baba, H. Aberrant methylation and silencing of IRF8 expression in non-small cell lung cancer. Oncol. Lett. 2014, 8, 1025–1030.
  44. Liang, J.; Lu, F.; Li, B.; Liu, L.; Zeng, G.; Zhou, Q.; Chen, L. IRF8 induces senescence of lung cancer cells to exert its tumor suppressive function. Cell Cycle 2019, 18, 3300–3312.
  45. Kesper, C.; Viestenz, A.; Wiese-Rischke, C.; Scheller, M.; Hammer, T. Impact of the transcription factor IRF8 on limbal epithelial progenitor cells in a mouse model. Exp. Eye Res. 2022, 218, 108985.
  46. Yang, D.; Thangaraju, M.; Greeneltch, K.; Browning, D.D.; Schoenlein, P.V.; Tamura, T.; Ozato, K.; Ganapathy, V.; Abrams, S.I.; Liu, K. Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. Cancer Res. 2007, 67, 3301–3309.
  47. McGough, J.M.; Yang, D.; Huang, S.; Georgi, D.; Hewitt, S.M.; Rocken, C.; Tanzer, M.; Ebert, M.P.; Liu, K. DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells. Mol. Cancer Res. 2008, 6, 1841–1851.
  48. Lipman, D.J.; Pearson, W.R. Rapid and sensitive protein similarity searches. Science 1985, 227, 1435–1441.
  49. Escalante, C.R.; Brass, A.L.; Pongubala, J.M.; Shatova, E.; Shen, L.; Singh, H.; Aggarwal, A.K. Crystal structure of PU.1/IRF-4/DNA ternary complex. Mol. Cell 2002, 10, 1097–1105.
  50. Langlais, D.; Barreiro, L.B.; Gros, P. The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J. Exp. Med. 2016, 213, 585–603.
  51. Tamura, T.; Kong, H.J.; Tunyaplin, C.; Tsujimura, H.; Calame, K.; Ozato, K. ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells. Blood 2003, 102, 4547–4554.
  52. Tamura, T.; Thotakura, P.; Tanaka, T.S.; Ko, M.S.; Ozato, K. Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. Blood 2005, 106, 1938–1947.
  53. Kuwata, T.; Gongora, C.; Kanno, Y.; Sakaguchi, K.; Tamura, T.; Kanno, T.; Basrur, V.; Martinez, R.; Appella, E.; Golub, T.; et al. Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element. Mol. Cell Biol. 2002, 22, 7439–7448.
  54. Yamamoto, M.; Kato, T.; Hotta, C.; Nishiyama, A.; Kurotaki, D.; Yoshinari, M.; Takami, M.; Ichino, M.; Nakazawa, M.; Matsuyama, T.; et al. Shared and distinct functions of the transcription factors IRF4 and IRF8 in myeloid cell development. PLoS ONE 2011, 6, e25812.
  55. Elfrink, S.; Ter Beest, M.; Janssen, L.; Baltissen, M.P.; Jansen, P.; Kenyon, A.N.; Steen, R.M.; de Windt, D.; Hagemann, P.M.; Hess, C.; et al. IRF8 is a transcriptional activator of CD37 expression in diffuse large B-cell lymphoma. Blood Adv. 2022, 6, 2254–2266.
  56. Kanno, Y.; Levi, B.Z.; Tamura, T.; Ozato, K. Immune cell-specific amplification of interferon signaling by the IRF-4/8-PU.1 complex. J. Interferon Cytokine Res. 2005, 25, 770–779.
  57. Kurotaki, D.; Osato, N.; Nishiyama, A.; Yamamoto, M.; Ban, T.; Sato, H.; Nakabayashi, J.; Umehara, M.; Miyake, N.; Matsumoto, N.; et al. Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation. Blood 2013, 121, 1839–1849.
  58. Kurotaki, D.; Tamura, T. Transcriptional and Epigenetic Regulation of Innate Immune Cell Development by the Transcription Factor, Interferon Regulatory Factor-8. J. Interferon Cytokine Res. 2016, 36, 433–441.
  59. Laricchia-Robbio, L.; Tamura, T.; Karpova, T.; Sprague, B.L.; McNally, J.G.; Ozato, K. Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages. Proc. Natl. Acad. Sci. USA 2005, 102, 14368–14373.
  60. Brass, A.L.; Kehrli, E.; Eisenbeis, C.F.; Storb, U.; Singh, H. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 1996, 10, 2335–2347.
  61. Brass, A.L.; Zhu, A.Q.; Singh, H. Assembly requirements of PU.1-Pip (IRF-4) activator complexes: Inhibiting function in vivo using fused dimers. EMBO J. 1999, 18, 977–991.
  62. Ozato, K.; Tsujimura, H.; Tamura, T. Toll-like receptor signaling and regulation of cytokine gene expression in the immune system. Biotechniques 2002, 33, S66–S75.
  63. Schmidt, M.; Bies, J.; Tamura, T.; Ozato, K.; Wolff, L. The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15(Ink4b) in murine myeloid cells. Blood 2004, 103, 4142–4149.
  64. Tsujimura, H.; Tamura, T.; Gongora, C.; Aliberti, J.; Reis e Sousa, C.; Sher, A.; Ozato, K. ICSBP/IRF-8 retrovirus transduction rescues dendritic cell development in vitro. Blood 2003, 101, 961–969.
  65. Dror, N.; Rave-Harel, N.; Burchert, A.; Azriel, A.; Tamura, T.; Tailor, P.; Neubauer, A.; Ozato, K.; Levi, B.Z. Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells. J. Biol. Chem. 2007, 282, 5633–5640.
  66. Humblin, E.; Thibaudin, M.; Chalmin, F.; Derangere, V.; Limagne, E.; Richard, C.; Flavell, R.A.; Chevrier, S.; Ladoire, S.; Berger, H.; et al. IRF8-dependent molecular complexes control the Th9 transcriptional program. Nat. Commun. 2017, 8, 2085.
  67. Glasmacher, E.; Agrawal, S.; Chang, A.B.; Murphy, T.L.; Zeng, W.; Vander Lugt, B.; Khan, A.A.; Ciofani, M.; Spooner, C.J.; Rutz, S.; et al. A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 2012, 338, 975–980.
  68. Li, P.; Spolski, R.; Liao, W.; Wang, L.; Murphy, T.L.; Murphy, K.M.; Leonard, W.J. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 2012, 490, 543–546.
  69. Tussiwand, R.; Lee, W.L.; Murphy, T.L.; Mashayekhi, M.; Kc, W.; Albring, J.C.; Satpathy, A.T.; Rotondo, J.A.; Edelson, B.T.; Kretzer, N.M.; et al. Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature 2012, 490, 502–507.
  70. Salem, S.; Salem, D.; Gros, P. Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases. Hum. Genet. 2020, 139, 707–721.
  71. Bovolenta, C.; Driggers, P.H.; Marks, M.S.; Medin, J.A.; Politis, A.D.; Vogel, S.N.; Levy, D.E.; Sakaguchi, K.; Appella, E.; Coligan, J.E.; et al. Molecular interactions between interferon consensus sequence binding protein and members of the interferon regulatory factor family. Proc. Natl. Acad. Sci. USA 1994, 91, 5046–5050.
  72. Nelson, N.; Marks, M.S.; Driggers, P.H.; Ozato, K. Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Mol. Cell Biol. 1993, 13, 588–599.
  73. Rosenbauer, F.; Waring, J.F.; Foerster, J.; Wietstruk, M.; Philipp, D.; Horak, I. Interferon consensus sequence binding protein and interferon regulatory factor-4/Pip form a complex that represses the expression of the interferon-stimulated gene-15 in macrophages. Blood 1999, 94, 4274–4281.
  74. Ramirez-Salazar, E.G.; Almeraya, E.V.; Lopez-Perez, T.V.; Jimenez-Salas, Z.; Patino, N.; Velazquez-Cruz, R. MicroRNA-1270 Inhibits Cell Proliferation, Migration, and Invasion via Targeting IRF8 in Osteoblast-like Cell Lines. Curr. Issues Mol. Biol. 2022, 44, 1182–1190.
  75. Rajabi, H.; Tagde, A.; Alam, M.; Bouillez, A.; Pitroda, S.; Suzuki, Y.; Kufe, D. DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene 2016, 35, 6439–6445.
  76. Luo, X.; Xiong, X.; Shao, Q.; Xiang, T.; Li, L.; Yin, X.; Li, X.; Tao, Q.; Ren, G. The tumor suppressor interferon regulatory factor 8 inhibits beta-catenin signaling in breast cancers, but is frequently silenced by promoter methylation. Oncotarget 2017, 8, 48875–48888.
  77. Yamashita, M.; Toyota, M.; Suzuki, H.; Nojima, M.; Yamamoto, E.; Kamimae, S.; Watanabe, Y.; Kai, M.; Akashi, H.; Maruyama, R. DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae. Cancer Sci. 2010, 101, 1708–1716.
  78. Lee, K.; Geng, H.; Ng, K.; Yu, J.; Van Hasselt, A.; Cao, Y.; Zeng, Y.; Wong, A.; Wang, X.; Ying, J. Epigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas. Oncogene 2008, 27, 5267–5276.
  79. Ye, L.; Xiang, T.; Zhu, J.; Li, D.; Shao, Q.; Peng, W.; Tang, J.; Li, L.; Ren, G. Interferon consensus sequence-binding protein 8, a tumor suppressor, suppresses tumor growth and invasion of non-small cell lung cancer by interacting with the wnt/β-catenin pathway. Cell. Physiol. Biochem. 2018, 51, 961–978.
  80. Wu, H.; You, L.; Li, Y.; Zhao, Z.; Shi, G.; Chen, Z.; Wang, Z.; Li, X.; Du, S.; Ye, W.; et al. Loss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance. Cancer Res. 2020, 80, 2927–2939.
  81. Zhang, Q.; Zhang, L.; Li, L.; Wang, Z.; Ying, J.; Fan, Y.; Xu, B.; Wang, L.; Liu, Q.; Chen, G.; et al. Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis. Cancer Lett. 2014, 354, 227–234.
  82. Zilionis, R.; Engblom, C.; Pfirschke, C.; Savova, V.; Zemmour, D.; Saatcioglu, H.D.; Krishnan, I.; Maroni, G.; Meyerovitz, C.V.; Kerwin, C.M.; et al. Single-Cell Transcriptomics of Human and Mouse Lung Cancers Reveals Conserved Myeloid Populations across Individuals and Species. Immunity 2019, 50, 1317–1334.e10.
  83. Mehner, C.; Miller, E.; Nassar, A.; Bamlet, W.R.; Radisky, E.S.; Radisky, D.C. Tumor cell expression of MMP3 as a prognostic factor for poor survival in pancreatic, pulmonary, and mammary carcinoma. Genes Cancer 2015, 6, 480.
  84. Mendes, O.; Kim, H.-T.; Stoica, G. Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin. Exp. Metastasis 2005, 22, 237–246.
  85. Shoshan, E.; Braeuer, R.R.; Kamiya, T.; Mobley, A.K.; Huang, L.; Vasquez, M.E.; Velazquez-Torres, G.; Chakravarti, N.; Ivan, C.; Prieto, V. NFAT1 directly regulates IL8 and MMP3 to promote melanoma tumor growth and metastasis. Cancer Res. 2016, 76, 3145–3155.
  86. Banik, D.; Netherby, C.S.; Bogner, P.N.; Abrams, S.I. MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction. Oncotarget 2015, 6, 15164–15179.
  87. Sung, J.Y.; Park, S.Y.; Kim, J.H.; Kang, H.G.; Yoon, J.H.; Na, Y.S.; Kim, Y.N.; Park, B.K. Interferon consensus sequence-binding protein (ICSBP) promotes epithelial-to-mesenchymal transition (EMT)-like phenomena, cell-motility, and invasion via TGF-β signaling in U2OS cells. Cell Death Dis. 2014, 5, e1224.
  88. Egwuagu, C.E.; Li, W.; Yu, C.R.; Che Mei Lin, M.; Chan, C.C.; Nakamura, T.; Chepelinsky, A.B. Interferon-gamma induces regression of epithelial cell carcinoma: Critical roles of IRF-1 and ICSBP transcription factors. Oncogene 2006, 25, 3670–3679.
  89. Villa-Morales, M.; Fernandez-Piqueras, J. Targeting the Fas/FasL signaling pathway in cancer therapy. Expert Opin. Ther. Targets 2012, 16, 85–101.
  90. Mollinedo, F.; Gajate, C. Fas/CD95 death receptor and lipid rafts: New targets for apoptosis-directed cancer therapy. Drug Resist. Updates 2006, 9, 51–73.
  91. Merting, A.D.; Poschel, D.B.; Lu, C.; Klement, J.D.; Yang, D.; Li, H.; Shi, H.; Chapdelaine, E.; Montgomery, M.; Redman, M.T.; et al. Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo. Cancers 2022, 14, 361.
  92. Xiao, W.; Ibrahim, M.L.; Redd, P.S.; Klement, J.D.; Lu, C.; Yang, D.; Savage, N.M.; Liu, K. Loss of Fas expression and function is coupled with colon cancer resistance to immune checkpoint inhibitor immunotherapy. Mol. Cancer Res. 2019, 17, 420–430.
  93. Yang, D.; Wang, S.; Brooks, C.; Dong, Z.; Schoenlein, P.V.; Kumar, V.; Ouyang, X.; Xiong, H.; Lahat, G.; Hayes-Jordan, A.; et al. IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression. Cancer Res. 2009, 69, 1080–1088.
  94. Yang, D.; Thangaraju, M.; Browning, D.D.; Dong, Z.; Korchin, B.; Lev, D.C.; Ganapathy, V.; Liu, K. IFN Regulatory Factor 8 Mediates Apoptosis in Nonhemopoietic Tumor Cells via Regulation of Fas Expression. J. Immunol. 2007, 179, 4775–4782.
  95. Seelan, R.S.; Qian, C.; Yokomizo, A.; Bostwick, D.G.; Smith, D.I.; Liu, W. Human acid ceramidase is overexpressed but not mutated in prostate cancer. Genes Chromosomes Cancer 2000, 29, 137–146.
  96. Saad, A.F.; Meacham, W.D.; Bai, A.; Anelli, V.; Anelli, V.; Mahdy, A.E.; Turner, L.S.; Cheng, J.; Bielawska, A.; Bielawski, J. The functional effects of acid ceramidase over-expression in prostate cancer progression and resistance to chemotherapy. Cancer Biol. Ther. 2007, 6, 1451–1456.
  97. Lucki, N.C.; Sewer, M.B. Genistein stimulates MCF-7 breast cancer cell growth by inducing acid ceramidase (ASAH1) gene expression. J. Biol. Chem. 2011, 286, 19399–19409.
  98. Mattei, F.; Schiavoni, G.; De Ninno, A.; Lucarini, V.; Sestili, P.; Sistigu, A.; Fragale, A.; Sanchez, M.; Spada, M.; Gerardino, A. A multidisciplinary study using in vivo tumor models and microfluidic cell-on-chip approach to explore the cross-talk between cancer and immune cells. J. Immunotoxicol. 2014, 11, 337–346.
  99. Klement, J.D.; Poschel, D.B.; Lu, C.; Merting, A.D.; Yang, D.; Redd, P.S.; Liu, K. Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression. Cancers 2021, 13, 1006.
  100. Klement, J.D.; Paschall, A.V.; Redd, P.S.; Ibrahim, M.L.; Lu, C.; Yang, D.; Celis, E.; Abrams, S.I.; Ozato, K.; Liu, K. An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. J. Clin. Investig. 2018, 128, 5549–5560.
  101. Lu, C.; Liu, Z.; Klement, J.D.; Yang, D.; Merting, A.D.; Poschel, D.; Albers, T.; Waller, J.L.; Shi, H.; Liu, K. WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape. J. Immunother. Cancer 2021, 9, e002624.
  102. Lee, J.L.; Wang, M.J.; Sudhir, P.R.; Chen, G.D.; Chi, C.W.; Chen, J.Y. Osteopontin promotes integrin activation through outside-in and inside-out mechanisms: OPN-CD44V interaction enhances survival in gastrointestinal cancer cells. Cancer Res. 2007, 67, 2089–2097.
  103. Nallasamy, P.; Nimmakayala, R.K.; Karmakar, S.; Leon, F.; Seshacharyulu, P.; Lakshmanan, I.; Rachagani, S.; Mallya, K.; Zhang, C.; Ly, Q.P.; et al. Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis. Gastroenterology 2021, 161, 1998–2013.e7.
  104. Qi, J.; Sun, H.; Zhang, Y.; Wang, Z.; Xun, Z.; Li, Z.; Ding, X.; Bao, R.; Hong, L.; Jia, W.; et al. Single-cell and spatial analysis reveal interaction of FAP(+) fibroblasts and SPP1(+) macrophages in colorectal cancer. Nat. Commun. 2022, 13, 1742.
  105. Liu, Y.; Zhang, Q.; Xing, B.; Luo, N.; Gao, R.; Yu, K.; Hu, X.; Bu, Z.; Peng, J.; Ren, X.; et al. Immune phenotypic linkage between colorectal cancer and liver metastasis. Cancer Cell 2022, 40, 424–437.e5.
  106. Rud, A.K.; Boye, K.; Oijordsbakken, M.; Lund-Iversen, M.; Halvorsen, A.R.; Solberg, S.K.; Berge, G.; Helland, A.; Brustugun, O.T.; Maelandsmo, G.M. Osteopontin is a prognostic biomarker in non-small cell lung cancer. BMC Cancer 2013, 13, 540.
  107. Rittling, S.R.; Chambers, A.F. Role of osteopontin in tumour progression. Br. J. Cancer 2004, 90, 1877–1881.
  108. Sreekanthreddy, P.; Srinivasan, H.; Kumar, D.M.; Nijaguna, M.B.; Sridevi, S.; Vrinda, M.; Arivazhagan, A.; Balasubramaniam, A.; Hegde, A.S.; Chandramouli, B.A.; et al. Identification of potential serum biomarkers of glioblastoma: Serum osteopontin levels correlate with poor prognosis. Cancer Epidemiol. Biomark. Prev. 2010, 19, 1409–1422.
  109. Chakraborty, G.; Jain, S.; Kundu, G.C. Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res. 2008, 68, 152–161.
  110. Sangaletti, S.; Tripodo, C.; Sandri, S.; Torselli, I.; Vitali, C.; Ratti, C.; Botti, L.; Burocchi, A.; Porcasi, R.; Tomirotti, A.; et al. Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res. 2014, 74, 4706–4719.
  111. Moorman, H.R.; Poschel, D.; Klement, J.D.; Lu, C.; Redd, P.S.; Liu, K. Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation. Cancers 2020, 12, 3379.
  112. Coppola, D.; Szabo, M.; Boulware, D.; Muraca, P.; Alsarraj, M.; Chambers, A.F.; Yeatman, T.J. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin. Cancer Res. 2004, 10, 184–190.
  113. Wei, J.; Marisetty, A.; Schrand, B.; Gabrusiewicz, K.; Hashimoto, Y.; Ott, M.; Grami, Z.; Kong, L.Y.; Ling, X.; Caruso, H.; et al. Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J. Clin. Investig. 2019, 129, 137–149.
  114. Agrawal, D.; Chen, T.; Irby, R.; Quackenbush, J.; Chambers, A.F.; Szabo, M.; Cantor, A.; Coppola, D.; Yeatman, T.J. Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J. Natl. Cancer Inst. 2002, 94, 513–521.
  115. Paschall, A.V.; Yang, D.; Lu, C.; Choi, J.H.; Li, X.; Liu, F.; Figueroa, M.; Oberlies, N.H.; Pearce, C.; Bollag, W.B.; et al. H3K9 Trimethylation Silences Fas Expression to Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance. J. Immunol. 2015, 195, 1868–1882.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Immunology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Hannah R. Moorman
,
Yazmin Reategui
,
Dakota B. Poschel
,
Kebin Liu
View Times: 566
Revisions: 2 times (View History)
Update Date: 31 Aug 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback