Skip to main content

Advertisement

SpringerLink
Log in

Constitutive type-1 interferons signaling activity in malignant gliomas

  • Research
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

Recent studies revealed a pro-tumor effect of constitutive Type-1 interferons (IFN-I) production and the downstream signaling activity in several malignancies. In contrast, heterogeneity and clinical significance of the signaling activity in gliomas remain unknown. Thus, we aimed to depict the heterogeneity and clinical significance of constitutive Type-1 interferon (IFN-I) production and the downstream signaling activity in gliomas.

Methods

We utilized multiplex immunofluorescence (mIF) on a 364 gliomas tissue microarray from our cohort. Moreover, we conducted bioinformatic analyses on the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases to investigate the heterogeneity and clinical significance of constitutive IFN-I signaling activity in gliomas.

Results

We observed high heterogeneity of the constitutive IFN-I signaling activity among glioma subtypes. Signaling increased with the WHO malignancy grade while decreasing in the gliomas with IDH mutations. Additionally, high IFN-I activity served as an independent predictor of unfavorable outcomes, and global DNA hypermethylation in IDH-mutant gliomas was associated with decreased IFN-I signaling activity. Positive correlations were observed between the IFN-I activity and glioma-associated inflammation, encompassing both anti-tumor and pro-tumor immune responses. Furthermore, the IFN-I activity varied significantly among tumor and immune cells in the glioma microenvironment (GME). Notably, a distinct pattern of IFN-I signaling activity distribution in GME cells was observed among glioma subtypes, and the pattern was independently associated with patient overall survival.

Conclusions

Constitutive IFN-I signaling activity varies significantly among glioma subtypes and represents a potential indicator for increased glioma inflammation and unfavorable clinical outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

Data available on request due to privacy/ethical considerations.

References

  1. Louis DN, Perry A, Wesseling P et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-Oncol 23:1231–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018. Neuro-Oncol 23:iii1-105

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M (2020) Management of glioblastoma: State of the art and future directions. CA Cancer J Clin 70:299–312

    Article  PubMed  Google Scholar 

  4. Lapointe S, Perry A, Butowski NA (2018) Primary brain tumours in adults. The Lancet 392:432–446

    Article  Google Scholar 

  5. Ansell SM, Lesokhin AM, Borrello I et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319

    Article  PubMed  Google Scholar 

  6. Yi M, Zheng X, Niu M, Zhu S, Ge H, Wu K (2022) Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer 21:28

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yang C, Austin F, Richard H et al (2019) Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome. Cold Spring Harb Mol Case Stud 5:a003863

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yin Z, Yu M, Ma T et al (2021) Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1. J Immunother Cancer 9:e001698

    Article  PubMed  PubMed Central  Google Scholar 

  9. Frederico SC, Hancock JC, Brettschneider EES, Ratnam NM, Gilbert MR, Terabe M (2021) Making a Cold Tumor Hot: The Role of Vaccines in the Treatment of Glioblastoma. Front Oncol [Internet]. [Cited 3 March 2022]; 11. https://www.frontiersin.org/article/10.3389/fonc.2021.672508

  10. Rameshbabu S, Labadie BW, Argulian A, Patnaik A (2021) Targeting innate immunity in cancer therapy. Vaccines 9:138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Motwani M, Pesiridis S, Fitzgerald KA (2019) DNA sensing by the cGAS–STING pathway in health and disease. Nat Rev Genet 20:657–674

    Article  CAS  PubMed  Google Scholar 

  12. Li Y, Wilson HL, Kiss-Toth E (2017) Regulating STING in health and disease. J Inflamm Lond Engl [Internet]. [Cited 3 March 2022]; 14. https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5463399/

  13. Sistigu A, Yamazaki T, Vacchelli E et al (2014) Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 20:1301–1309

    Article  CAS  PubMed  Google Scholar 

  14. Ito T, Amakawa R, Inaba M, Ikehara S, Inaba K, Fukuhara S (1950) Differential regulation of human blood dendritic cell subsets by IFNs. J Immunol Baltim Md 2001(166):2961–2969

    Google Scholar 

  15. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G (2015) Type I interferons in anticancer immunity. Nat Rev Immunol 15:405–414

    Article  CAS  PubMed  Google Scholar 

  16. Huber JP, Farrar JD (2011) Regulation of effector and memory T-cell functions by type I interferon. Immunology 132:466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Antonelli G, Scagnolari C, Moschella F, Proietti E (2015) Twenty-five years of type I interferon-based treatment: A critical analysis of its therapeutic use. Cytokine Growth Factor Rev 26:121–131

    Article  CAS  PubMed  Google Scholar 

  18. Agarwala SS, O’Day SJ (2011) Current and future adjuvant immunotherapies for melanoma: blockade of cytotoxic T-lymphocyte antigen-4 as a novel approach. Cancer Treat Rev 37:133–142

    Article  PubMed  Google Scholar 

  19. Haller O, Kochs G (2011) Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res Off J Int Soc Interferon Cytokine Res 31:79–87

    Article  CAS  Google Scholar 

  20. Woo S-R, Fuertes MB, Corrales L et al (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Silginer M, Nagy S, Happold C, Schneider H, Weller M, Roth P (2017) Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma. Neuro-Oncol 19:1338–1349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ma H, Yang W, Zhang L et al (2019) Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma. Br J Cancer 120:317–330

    Article  CAS  PubMed  Google Scholar 

  23. Duarte CW, Willey CD, Zhi D et al (2012) Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. PLoS ONE 7:e29653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang Y, Li C, Chi X et al (2022) Low MxA expression predicts better immunotherapeutic outcomes in glioblastoma patients receiving heat shock protein peptide complex 96 vaccination. Front Oncol 12:865779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Haller O, Stertz S, Kochs G (2007) The Mx GTPase family of interferon-induced antiviral proteins. Microbes Infect 9:1636–1643

    Article  CAS  PubMed  Google Scholar 

  27. Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: A complex web of host defenses. Annu Rev Immunol 32:513–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ho SSW, Zhang WYL, Tan NYJ et al (2016) The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells. Immunity 44:1177–1189

    Article  CAS  PubMed  Google Scholar 

  29. Li W, Lu L, Lu J et al (2020) cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy. Sci Transl Med 12:eaay9013

    Article  CAS  PubMed  Google Scholar 

  30. Turcan S, Rohle D, Goenka A et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang S, Li R, Huang X et al (2019) Association study between methylation in the promoter regions of cGAS, MAVS, and TRAF3 genes and the risk of cervical precancerous lesions and cervical cancer in a southern chinese population. Front Genet 10:1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. J L, I K, J L et al (2023) Harnessing type I interferon-mediated immunity to target malignant brain tumors. Front Immunol [Internet]. [Cited 31 December 2023]; 14. https://pubmed.ncbi.nlm.nih.gov/37304294/

  33. Bagaev A, Kotlov N, Nomie K et al (2021) Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 39:845-865.e7

    Article  CAS  PubMed  Google Scholar 

  34. Ivashkiv LB, Donlin LT (2014) Regulation of type I interferon responses. Nat Rev Immunol 14:36–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yan Y, Zheng L, Du Q et al (2021) Interferon regulatory factor 1(IRF-1) activates anti-tumor immunity via CXCL10/CXCR3 axis in hepatocellular carcinoma (HCC). Cancer Lett 506:95–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Erttmann SF, Swacha P, Aung KM et al (2022) The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity 55:847-861.e10

    Article  CAS  PubMed  Google Scholar 

  37. Gutterman JU, Blumenschein GR, Alexanian R et al (1980) Leukocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma, and malignant lymphoma. Ann Intern Med 93:399–406

    Article  CAS  PubMed  Google Scholar 

  38. Zhan X, Guo S, Li Y et al (2020) Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma. J Exp Med 217:e20191340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gong W, Donnelly CR, Heath BR et al (2021) Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion. Onco Targets Ther 10(1):1997385

  40. Ahmed D, Cassol E (2017) Role of cellular metabolism in regulating type I interferon responses: Implications for tumour immunology and treatment. Cancer Lett 409:20–29

    Article  CAS  PubMed  Google Scholar 

  41. Zhou L, Zhang Y, Wang Y et al (2020) A dual role of type i interferons in antitumor immunity. Adv Biosyst 4:e1900237

    Article  PubMed  Google Scholar 

  42. Kohanbash G, Carrera DA, Shrivastav S et al (2017) Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest 127:1425–1437

    Article  PubMed  PubMed Central  Google Scholar 

  43. Richardson LG, Nieman LT, Stemmer-Rachamimov AO et al (2020) IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice. Oncoimmunology 9:1806662

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zhang L, Sorensen MD, Kristensen BW, Reifenberger G, McIntyre TM, Lin F (2018) D-2-Hydroxyglutarate is an intercellular mediator in IDH-mutant gliomas inhibiting complement and T cells. Clin Cancer Res Off J Am Assoc Cancer Res 24:5381–5391

    Article  CAS  Google Scholar 

  45. Duong E, Fessenden TB, Lutz E et al (2022) Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity. Immunity 55:308-323.e9

    Article  CAS  PubMed  Google Scholar 

  46. Johnson KC, Anderson KJ, Courtois ET et al (2021) Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response. Nat Genet 53:1456–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liang H, Deng L, Hou Y et al (2017) Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun 8:1736

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We express our sincere gratitude to Dr. Junmei Wang from the Department of Pathology at Beijing Neurosurgical Institute, Capital Medical University, for providing valuable expertise in confirming the pathological diagnosis for the cases included in the microarray analysis. The authors thank AiMi Academic Services (http://www.aimieditor.com) for English language editing and review services.

Funding

This work was supported by National Natural Science Foundation of China, Grant/Award Number: 81702451.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Fengtai District, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Beijing, 100070, China

    Chunzhao Li, Lang Long, Yi Wang, Xiaohan Chi, Peng Zhang, Yang Zhang & Nan Ji

  2. China National Clinical Research Center for Neurological Diseases, Beijing, China

    Chunzhao Li, Lang Long, Yi Wang, Xiaohan Chi, Peng Zhang, Yang Zhang & Nan Ji

  3. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China

    Yi Wang & Nan Ji

Authors
  1. Chunzhao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lang Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaohan Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nan Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Nan Ji and Yang Zhang made substantial contributions to the conception or design of the work. mIF, data collection and analysis were performed by Chunzhao Li, Lang Long and Yi Wang. The first draft of the manuscript was written by Lang Long and Chunzhao Li, all authors commented on previous versions of the manuscript. All authors read and approved the version to be published.

Corresponding authors

Correspondence to Yang Zhang or Nan Ji.

Ethics declarations

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics Committee of Beijing Tiantan Hospital (KY2014-021–02).

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Chunzhao Li, and Lang Long share first authorship.

Yang Zhang, and Nan Ji are joint senior authors.

Supplementary Information

Below is the link to the electronic supplementary material.

11060_2024_4601_MOESM1_ESM.eps

Supplementary Figure 1 Landscape of constitutive IFN-I signaling activity. (A) ISG score distribution across CGGA cohort (n=1018). Spearman and Wilcoxon tests applied for age correlation and group differences, respectively. (B) Box plot of ISG scores stratified by Grade and IDH status in CGGA dataset. Analysis excludes cases with missing Grade or IDH information. Wilcoxon test used for statistical comparison. (C) Correlation between ISG score and MX1 expression in CGGA dataset, stratified by Grade and IDH status. Spearman's test applied for analysis. (D) MxA distribution across TMA cohort (n=364). Spearman and Wilcoxon tests applied for age correlation and group differences, respectively. (E) Kaplan-Meier survival analysis of CGGA dataset, dividing patients into high and low ISG score groups based on median value. Survival differences evaluated using log-rank test. (F) Univariate and multivariate cox regression model of prognostic factors associated with CGGA gliomas. (EPS 7425 KB)

11060_2024_4601_MOESM2_ESM.eps

Supplementary Figure 2 Correlation between cGAS-STING axis and IDH status and Grade in gliomas. (A-B) Box plot of cGAS mRNA expression levels and promoter methylation levels stratified by Grade and IDH status in CGGA dataset. Analysis excludes cases with missing Grade or IDH information. Wilcoxon test used for statistical comparison. (C-H) Difference between promoter methylation levels (C-E) and transcriptional levels (F-H) of STING, IRF3, and TBK1 genes involved in the cGAS-STING axis and IDH status in the TCGA dataset. The samples were stratified by WHO malignancy grade. (EPS 5621 KB)

11060_2024_4601_MOESM3_ESM.eps

Supplementary Figure 3. Constitutive IFN-I signaling and related glioma-associated inflammation. We conducted a comprehensive analysis of ssGSEA scores across these datasets and glioma types (A-C). For each panel, ssGSEA scores within each pathway were normalized. Additionally, Spearman correlations and significance levels for ISG and ssGSEA scores for each pathway are displayed beside each heatmap. (A) Heatmap of 7 pathways in two functional categories for IDH-mutant LGGs and IDH wild-type GBMs in the TCGA dataset. (B) Heatmap of 29 pathways in four functional categories for IDH-mutant LGGs and IDH wild-type GBMs in the CGGA dataset. (C) Heatmap of 29 pathways in four functional categories for Glioblastomas in the CPTAC dataset. (EPS 13770 KB)

Supplementary file4 (DOCX 14 KB)

Supplementary file5 (DOCX 15 KB)

Supplementary file6 (DOCX 18 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, C., Long, L., Wang, Y. et al. Constitutive type-1 interferons signaling activity in malignant gliomas. J Neurooncol 168, 381–391 (2024). https://doi.org/10.1007/s11060-024-04601-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-024-04601-w

Keywords

Search

Navigation