Skip to main content

Advertisement

SpringerLink
Log in

PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Interferon-γ (IFN-γ) is conventionally regarded as an inflammatory cytokine that has a pivotal role in anti-infection and tumor immune surveillance. It has been used clinically to treat a variety of malignancies. However, increased evidence has suggested IFN-γ can act to induce tumor progression. The role of IFN-γ in regulating antitumor immunity appears to be complex and paradoxical. The mechanism underlying the dual aspects of IFN-γ function in antitumor immunity is not clear.

Methods

(1) Lung cancer cells (A549 cells) were cultured with pleural effusion or supernatant of tumor-associated macrophages (TAMs supernatant), and the expression levels of PD-L1 were detected by flow cytometer. The invasion capacity was measured in vitro using trans-well migration assays. (2) Pleural effusion mononuclear cells (PEMC) were separated by Ficoll Hypaque gradient. The expression of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and INF-γ in the tumor-associated macrophages was analyzed by flow cytometry. (3) A549 cells were stimulated with IL-6, IL-10, TNF-α, or IFN-γ and then the expression levels were detected by flow cytometry. (4) The expression levels of phospho-ERK (p-ERK), phospho-AKT (p-AKT), and phospho-Sat3 (p-Stat3) were analyzed with Western blot after stimulation with IFN-γ. (5) Cotreatment of the A549 cells with MAPK/ERK-specific inhibitor PD98059, PI3K/AKT-specific inhibitor LY294002, or JAK/STAT3-specific inhibitor AG490, respectively, blocked IFN-γ-induced PD-L1 expression, and then PD-L1 expression was detected by flow cytometry.

Results

We demonstrated that TAMs could induce the expression of PD-L1 by the secretion of IFN-γ through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in A549 cells. Furthermore, the signal pathway blockers LY294002 or AG490 could block the induced expression of PD-L1 by IFN-γ.

Conclusions

IFN-γ was not always successful as an antitumor agent. It also can promote tumor cells to evade immune surveillance. Researchers should be cautious in using IFN-γ as a therapeutic agent for cancer treatment.

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
Fig. 6

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  2. Zhang D, Chen Z, Wang DC, Wang X (2015) Regulatory T cells and potential inmmunotherapeutic targets in lung cancer. Cancer Metastasis Rev 34:277–290

    Article  CAS  PubMed  Google Scholar 

  3. Niedobitek G, Barros MH, Dreyer JH et al (2015) Tumor-associated macrophages: function and differentiation. Pathologe 36:477–484

    Article  CAS  PubMed  Google Scholar 

  4. Parker KH, Beury DW, Ostrand-Rosenberg S (2015) Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 128:95–139

    Article  PubMed  PubMed Central  Google Scholar 

  5. Obeid E, Nanda R, Fu YX et al (2013) The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol 43:5–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li H, Yang B, Huang J et al (2015) Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells. Oncotarget 6:29637–29650

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rai RK, Vishvakarma NK, Mohapatra TM et al (2012) Augmented macrophage differentiation and polarization of tumor-associated macrophages towards M1 subtype in Listeria-administered tumor-bearing host. J Immunother 35:544–554

    Article  CAS  PubMed  Google Scholar 

  8. Heusinkveld M, de Vos van Steenwijk PJV, Goedemans R et al (2011) M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4 + Th1 cells. J Immunol 187(3):1157–1165

    Article  CAS  PubMed  Google Scholar 

  9. Mantovani A, Sozzani S, Locati M et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  CAS  PubMed  Google Scholar 

  10. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78

    Article  CAS  PubMed  Google Scholar 

  11. Schmidt LH, Kummel A, Gorlich D et al (2015) PD-1 and PD-L1 expression in NSCLC indicate a favorable prognosis in defined subgroups. PLoS One 10:e0136023

    Article  PubMed  PubMed Central  Google Scholar 

  12. Park JJ, Omiya R, Matsumura Y et al (2010) B7-H1/CD80 interaction is required for the induction and maintenance of peripheral peripheral T-cell tolerance. Blood 116(8):1291–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Paterson AM, Brown KE, Keir ME et al (2011) The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol 187:1097–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348:56–61

    Article  CAS  PubMed  Google Scholar 

  15. Sui X, Ma J, Han W et al (2015) The anticancer immune response o anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget 6:19393–19404

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hamanishi J, Mandai M, Ikeda T et al (2015) Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol 33:4015–4022

    Article  CAS  PubMed  Google Scholar 

  17. Selenko-Gebauer N, Majdic O, Szekeres A et al (2003) B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol 170(7):3637–3644

    Article  CAS  PubMed  Google Scholar 

  18. Lee SJ, Jang BC, Lee SW et al (2006) Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FFBS Lett 580(3):755–762

    Article  CAS  Google Scholar 

  19. Dijkmans R, Billiau A (1988) Interferon gamma: a master key in the immune system. Curr Opin Immunol 1:269–274

    Article  CAS  PubMed  Google Scholar 

  20. Zaidi MR, Merlino G (2011) The two faces of interferon-γ in cancer. Clin Cancer Res 17(19):6118–6124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Windbichler GH, Hausmaninger H, Stummvoll W et al (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer 82(6):1138–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mandai M, Hamanishi J, Abiko K et al (2016) Dual faces of IFN-γ in cancer progression: a role of PD-L1 induction in the determination of pro- and anti-tumor immunity. Clin Cancer Res 22(10):2329–2334

    Article  CAS  PubMed  Google Scholar 

  23. Xiao M, Wang C, Zhang J et al (2009) IFN-gamma promotes papilloma development by upregulating Th17-associated inflammation. Cancer Res 69(5):2010–2017

    Article  CAS  PubMed  Google Scholar 

  24. Meyskens FL Jr, Kopecky KJ, Taylor CW et al (1995) Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. J Natl Cancer Inst 87:1710–1713

    Article  PubMed  Google Scholar 

  25. Alberts DS, Marth C, Alvarez RD et al (2008) Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: results from a prospectively designed analysis of progression-free survival. Gynecol Oncol 109(2):174–181

    Article  CAS  PubMed  Google Scholar 

  26. Matsuura H, Sakaue M, Subbaramaiah K et al (1999) Regulation of cyclooxygenase-2 by interferon gamma and transforming growth factor alpha in normal human epidermal keratinocytes and squamous carcinoma cells. Role of mitogen-activated protein kinases. J Biol Chem 274:29138–29148

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Y, Zhang J, Xu K et al (2013) PTEN/PI3K/mTOR/B7-H1 signaling pathway regulates cell progression and immuno-resistance in pancreatic cancer. Hepatogastroenterology 60:1766–1772

    CAS  PubMed  Google Scholar 

  28. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rech AJ, Vonderheide RH (2013) Dynamic interplay of oncogenes and T cells induces PD-L1 in the tumor microenvironment. Cancer Discov 3:1330–1332

    Article  CAS  PubMed  Google Scholar 

  30. Taube JM, Anders RA, Young GD et al (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4:127ra137

    Article  Google Scholar 

  31. Irmler IM, Gajda M, Brauer R (2007) Exacerbation of antigen-induced arthritis in IFN-gamma-deficient mice as a result of unrestricted IL-17 response. J Immunol 179:6228–6236

    Article  CAS  PubMed  Google Scholar 

  32. Prendergast GC (2008) Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27:3889–3900

    Article  CAS  PubMed  Google Scholar 

  33. Katz JB, Muller AJ, Prendergast GC (2008) Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 222:206–221

    Article  CAS  PubMed  Google Scholar 

  34. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Morel S, Levy F, Burlet-Schiltz O et al (2000) Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity 12:107–117

    Article  CAS  PubMed  Google Scholar 

  36. Lee SJ, Jang BC, Lee SW et al (2006) Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274). FEBS Lett 580:755–762

    Article  CAS  PubMed  Google Scholar 

  37. Barach YS, Lee JS, Zang X (2011) T cell coinhibition in prostate cancer: new immune evasion pathways and emerging therapeutics. Trends Mol Med 17:47–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schalper KA (2014) PD-L1 expression and tumor-infiltrating lymphocytes: revisiting the antitumor immune response potential in breast cancer. Oncoimmunology 3:e29288

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was funded by the National Natural Science Foundation of China (31270940 to J.-A. Huang), Clinical Medical Center of Suzhou (Szzx201502), Suzhou Key Laboratory for Respiratory Medicine (No. SZS201617); the Societal and Developmental Project of Suzhou (No. SS201630); and The Foundation of Health Care Rejuvenation by Science and Education (KJXW2016003 to Y.-Y. Zeng) and Clinical Key Specialty Project of China.

Author information

Author notes

  1. Xiaohui Zhang and Yuanyuan Zeng contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215123, People’s Republic of China

    Xiaohui Zhang, Yuanyuan Zeng, Jianjie Zhu, Zeyi Liu, Weiwei Ning, Hui Zeng, Nan Zhang, Wenwen Du, Cheng Chen & Jian-an Huang

  2. Institute of Respiratory Diseases, Soochow University, Suzhou, People’s Republic of China

    Yuanyuan Zeng, Jianjie Zhu, Zeyi Liu & Jian-an Huang

  3. The Biotechnology Research Institute of Soochow University, Suzhou, People’s Republic of China

    Qiuxia Qu

Authors
  1. Xiaohui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuanyuan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiuxia Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianjie Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zeyi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiwei Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wenwen Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jian-an Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Cheng Chen or Jian-an Huang.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical standards

This work was approved to be performed by the Ethics Committee of the First Affiliated Hospital of Soochow University.

Informed consent

Informed consent was obtained from all individual participants included in the study.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Zeng, Y., Qu, Q. et al. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol 22, 1026–1033 (2017). https://doi.org/10.1007/s10147-017-1161-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-017-1161-7

Keywords

Search

Navigation