Skip to main content

Advertisement

SpringerLink
Log in

Ectopic PD-L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of STAT3 and STAT5

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

A Correction to this article was published on 14 July 2020

This article has been updated

Abstract

Escalated PD-L1 expression has been identified during malignant transformation in a number of cancer types and helps cancer cells escape an effective anti-tumor immune response. The mechanisms underlying escalated production of PD-L1 in many cancers, however, are still far from clear. We studied PD-L1, STAT3 and STAT5 mRNA expression using qRT-PCR in 72 BCR/ABL1 negative myeloproliferative neoplasm (MPN) patients (39 polycythemia vera and 33 essential thrombocythemia). Furthermore, phosphorylation status of STAT3 and STAT5 was studied using immunoblotting in the same patients. All MPN patients were first screened for JAK2 (V617F) mutation by tetra-primer ARMS-PCR, followed by quantification of JAK2 (V617F) mutation burden in all V617F positive MPN patients by ASO-PCR. Patients were screened for BCR/ABL1 fusion gene transcripts to rule out Ph positive status. Our findings showed that mRNA levels of PD-L1 and STAT3 were significantly higher in JAK2 (V617F) MPN patients, while as STAT5 was insignificantly upregulated. STAT3 and STAT5 phosphorylation was seen to be higher in JAK2 (V617F) MPN patients compared to the JAK2 (WT) patients. Upregulation of PD-L1, STAT3 and STAT5 was significantly associated with JAK2 (V617F) percentage in MPN patients. PD-L1, STAT3 and STAT5 expression significantly and positively correlated with JAK2 (V617F) allele burden. In addition, significant coexpression of PD-L1 with STAT3 and STAT5 was observed in MPN patients. In summary, JAK2 (V617F) mutation is accompanied by increased PD-L1 expression and this PD-L1 over expression is mediated by JAK2 (V617F) mainly through STAT3, while as STAT5 may play a minor role.

Graphic abstract

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

Similar content being viewed by others

Change history

  • 14 July 2020

    In the original publication, third author name was incorrectly published as “Ab Rashid Mir”. The correct name should read as “Rashid Mir”.

References

  1. Chemnitz JM, et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173(2):945–54.

    Article  CAS  PubMed  Google Scholar 

  2. Dong H, et al. B7–H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9.

    Article  CAS  PubMed  Google Scholar 

  3. Velcheti V, Rimm DL, Schalper KA. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1). J Thorac Oncol. 2013;8(6):803–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Velcheti V, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Investig. 2014;94(1):107–16.

    Article  CAS  PubMed  Google Scholar 

  5. Hamanishi J, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007;104(9):3360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hamanishi J, et al. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016;21(3):462–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thompson RH, et al. Costimulatory B7–H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA. 2004;101(49):17174–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shen JK, et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2(7):690–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Norde WJ, et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Can Res. 2011;71(15):5111–222.

    Article  CAS  Google Scholar 

  10. Michot JM, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.

    Article  CAS  PubMed  Google Scholar 

  11. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  12. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol. 2012;23(Supp1 8):viii5–21.

    Google Scholar 

  13. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dunn GP, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.

    Article  CAS  PubMed  Google Scholar 

  16. Mapara MY, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol. 2004;22(6):1136–51.

    Article  CAS  PubMed  Google Scholar 

  17. Marincola FM, et al. Tumors as elusive targets of T cell-based active immunotherapy. Trends Immunol. 2003;24(6):335–42.

    Article  CAS  PubMed  Google Scholar 

  18. Hersey P, Zhang XD. How melanoma cells evade trail-induced apoptosis. Nat Rev Cancer. 2001;1(2):142–50.

    Article  CAS  PubMed  Google Scholar 

  19. Lonchay C, et al. Correlation between tumor regression and T cell responses in melanoma patients vaccinated with a MAGE antigen. Proc Natl Acad Sci USA. 2004;101(Suppl 2):14631–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311–9.

    Article  PubMed  CAS  Google Scholar 

  21. Chen R, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Prestipino A, et al. Oncogenic JAK2(V617F) causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med. 2018;10(429):eaam7729.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    Article  CAS  PubMed  Google Scholar 

  24. Barbui T, et al. The 2016 revision of WHO classification of myeloproliferative neoplasms: clinical and molecular advances. Blood Rev. 2016;30(6):453–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24(6):1128–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Baxter EJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.

    Article  CAS  PubMed  Google Scholar 

  27. James C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.

    Article  CAS  PubMed  Google Scholar 

  28. Vannucchi AM, et al. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008;22(7):1299–307.

    Article  CAS  PubMed  Google Scholar 

  29. Passamonti F, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24(9):1574–9.

    Article  CAS  PubMed  Google Scholar 

  30. Tefferi A. Mutant molecules of interest in myeloproliferative neoplasms: introduction. Acta Haematol. 2008;119(4):192–3.

    Article  PubMed  Google Scholar 

  31. Passamonti F, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood. 2006;107(9):3676–82.

    Article  CAS  PubMed  Google Scholar 

  32. Scott LM, et al. Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood. 2006;108(7):2435–7.

    Article  CAS  PubMed  Google Scholar 

  33. Tefferi A, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer. 2006;106(3):631–5.

    Article  CAS  PubMed  Google Scholar 

  34. Vannucchi AM, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia. 2007;21(9):1952–9.

    Article  CAS  PubMed  Google Scholar 

  35. Vannucchi AM, et al. Clinical profile of homozygous JAK2 617V%3eF mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840–6.

    Article  CAS  PubMed  Google Scholar 

  36. Alvarez-Larran A, et al. Postpolycythaemic myelofibrosis: frequency and risk factors for this complication in 116 patients. Br J Haematol. 2009;146(5):504–9.

    Article  CAS  PubMed  Google Scholar 

  37. Passamonti F, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood. 2008;111(7):3383–7.

    Article  CAS  PubMed  Google Scholar 

  38. Kralovics R, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–900.

    Article  CAS  PubMed  Google Scholar 

  39. Marzec M, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1). Proc Natl Acad Sci USA. 2008;105(52):20852–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wolfle SJ, et al. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol. 2011;41(2):413–24.

    Article  PubMed  CAS  Google Scholar 

  41. Rosenberg JE, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Butte MJ, et al. Programmed death-1 ligand 1 interacts specifically with the B7–1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ohaegbulam KC, et al. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24–33.

    Article  CAS  PubMed  Google Scholar 

  45. Topalian SL, et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jones AV, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106(6):2162–8.

    Article  CAS  PubMed  Google Scholar 

  48. Guru SA, et al. PDGFRalpha promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: a study from India. Tumour Biol. 2017;39(10):1010428317713857.

    Article  PubMed  CAS  Google Scholar 

  49. Hochberg EP, et al. A novel rapid single nucleotide polymorphism (SNP)-based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation. Blood. 2003;101(1):363–9.

    Article  CAS  PubMed  Google Scholar 

  50. Paterson AM, et al. The programmed death-1 ligand 1:B7–1 pathway restrains diabetogenic effector T cells in vivo. J Immunol. 2011;187(3):1097–105.

    Article  CAS  PubMed  Google Scholar 

  51. Inman BA, et al. Atezolizumab: A PD-L1-blocking antibody for bladder cancer. Clin Cancer Res. 2017;23(8):1886–900.

    Article  CAS  PubMed  Google Scholar 

  52. Deng R, et al. Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor. mAbs. 2016;8(3):593–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stewart R, et al. Identification and characterization of MEDI4736, an antagonistic Anti-PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3(9):1052–62.

    Article  CAS  PubMed  Google Scholar 

  54. Mok T, et al. 192TiP: NEPTUNE: a global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy versus standard of care (SoC) platinum-based chemotherapy in the first-line treatment of patients (pts) with advanced or metastatic NSCLC. J Thorac Oncol. 2016;11:S140–S141141.

    Article  Google Scholar 

  55. Kolbusz RV, et al. Exaggerated response to insect bites. An unusual cutaneous manifestation of chronic lymphocytic leukemia. Int J Dermatol. 1989;28(3):186–7.

    Article  CAS  PubMed  Google Scholar 

  56. Grenga I, et al. A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T cell responses. Clin Transl Immunol. 2016;5(5):e83.

    Article  CAS  Google Scholar 

  57. Boyerinas B, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3(10):1148–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fujii R, et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget. 2016;7(23):33498–511.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kataoka K, et al. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature. 2016;534(7607):402–6.

    Article  CAS  PubMed  Google Scholar 

  60. Xie QK, et al. Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma. Oncoimmunology. 2016;5(7):e1181252.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Ikeda S, et al. PD-L1 Is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol. 2016;11(1):62–71.

    Article  PubMed  Google Scholar 

  62. Lee SJ, et al. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7–H1 (CD274). FEBS Lett. 2006;580(3):755–62.

    Article  CAS  PubMed  Google Scholar 

  63. Shin DS, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7(2):188–201.

    Article  CAS  PubMed  Google Scholar 

  64. Garcia-Diaz A, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19(6):1189–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Sameer Ahmad Guru acknowledges Indian Council of Medical Research (ICMR), Government of India (GOI) for providing financial support to carry out the research. He further extends his gratitude towards Multidisciplinary Research Unit (MRU), MAMC, New Delhi for providing lab space to carry out part of experimental work. We also extend our thanks to technical staff especially Mrs. Shobha for maintaining the aseptic conditions in laboratory.

Funding

Authors do not have any financial relationship with the organization that sponsored the research.

Author information

Authors and Affiliations

  1. Multidisciplinary Research Unit (MRU), Maulana Azad Medical College and Associated Hospitals, Bahadur Shah Zafar Marg, New Delhi, 110002, India

    Sameer Ahamd Guru

  2. Department of Gastroinstestinal Surgery, Govind Balab Pant Postgraduate Institute of Medical Education and Research (GIPMER), New Delhi, India

    Mamta P. Sumi

  3. University of Tabuk, Tabuk, Saudi Arabia

    Rashid Mir

  4. Centre of Research for Development (CORD), University of Kashmir, Srinagar, India

    Ajaz Ahmad Waza

  5. Institute of Pharmacology and Toxicology-Neuropharmacology, University of Zurich Winterthurerstrasse, Zurich, Switzerland

    Musadiq Ahmad Bhat

  6. University of Illinois At Chicago College of Medicine, Chicago, USA

    Mariyam Zuberi

  7. Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, Bahadur Shah Zafar Marg, New Delhi, 110002, India

    Promod Lali & Alpana Saxena

Authors
  1. Sameer Ahamd Guru
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mamta P. Sumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rashid Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ajaz Ahmad Waza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Musadiq Ahmad Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mariyam Zuberi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Promod Lali
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alpana Saxena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alpana Saxena.

Ethics declarations

Conflict of interest

All the authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Institutional Ethics Committee (IEC) of Maulana Azad Medical College (MAMC) and associated Hospitals; Lok Nayak Jay Prakash (LNJP), Govind Balab Pant Institute of Postgraduate Medical Education and Research (GIPMER), Guru Nanak Eye Centre, New Delhi, India (registered with Drug Controller General of India, Directorate of General Health Services, New Delhi) with study approval number issued F.1/IEC/MAMC/ (38)/4/2017/No: 211.

Informed consent

Our sincere and deep gratitude goes to all the patients included in this study for giving consent and making this study possible.

Additional information

Publisher's Note

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

The original version of this article was revised due to correct the third author name.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guru, S.A., Sumi, M.P., Mir, R. et al. Ectopic PD-L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of STAT3 and STAT5. Human Cell 33, 1099–1111 (2020). https://doi.org/10.1007/s13577-020-00370-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-020-00370-6

Keywords

Search

Navigation