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Cancer Immunology, Immunotherapy

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Open Access 01-07-2020 | Neurofibromatosis Type 1 | Original Article

Upregulated immuno-modulator PD-L1 in malignant peripheral nerve sheath tumors provides a potential biomarker and a therapeutic target

Authors: Said Farschtschi, Lan Kluwe, Su-Jin Park, Su-Jun Oh, Nancy Mah, Victor-Felix Mautner, Andreas Kurtz

Published in: Cancer Immunology, Immunotherapy | Issue 7/2020

Abstract

Background

Malignant peripheral nerve sheath tumors (MPNSTs) are rare aggressive sarcomas with poor prognosis. More than half of MPNSTs develop from benign precursor tumors associated with neurofibromatosis type 1 (NF1) which is a tumor suppressor gene disorder. Early detection of malignant transformation in NF1 patients is pivotal to improving survival. The primary aim of this study was to evaluate the role of immuno-modulators as candidate biomarkers of malignant transformation in NF1 patients with plexiform neurofibromas as well as predictors of response to immunotherapeutic approaches.

Methods

Sera from a total of 125 NF1 patients with quantified internal tumor load were included, and 25 of them had MPNSTs. A total of six immuno-modulatory factors (IGFBP-1, PD-L1, IFN-α, GM-CSF, PGE-2, and AXL) were measured in these sera using respective ELISA.

Results

NF1 patients with MPNSTs had significantly elevated PD-L1 levels in their sera compared to NF1 patients without MPNSTs. By contrast, AXL concentrations were significantly lower in sera of NF1-MPNST patients. IGFBP-1 and PGE2 serum levels did not differ between the two patient groups. IFN-α and GM-CSF were below the detectable level in most samples.

Conclusion

The immuno-modulator PD-L1 is upregulated in MPNST patients and therefore may provide as a potential biomarker of malignant transformation in patients with NF1 and as a response predictor for immunotherapeutic approaches.

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Brems H, Beert E, de Ravel T et al (2009) Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol 10(5):508–515. https://doi.org/10.1016/S1470-2045(09)70033-6 CrossRefPubMed

Evans DGR, Baser ME, McGaughran J et al (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39(5):311–314. https://doi.org/10.1136/jmg.39.5.311 CrossRefPubMedPubMedCentral

Upadhyaya MCDN (ed) (1998) Neurofibromatosis type 1: from genotype to phenotype. BIOS Scientific, Oxford

Ducatman BS, Scheithauer BW, Piepgras DG et al (1986) Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57(10):2006–2021. https://doi.org/10.1002/1097-0142(19860515)57:10%3c2006:aid-cncr2820571022%3e3.0.co;2-6 CrossRefPubMed

Grobmyer SR, Reith JD, Shahlaee A et al (2008) Malignant peripheral nerve sheath tumor: molecular pathogenesis and current management considerations. J Surg Oncol 97(4):340–349. https://doi.org/10.1002/jso.20971 CrossRefPubMed

Williams VC, Lucas J, Babcock MA et al (2009) Neurofibromatosis type 1 revisited. Pediatrics 123(1):124–133. https://doi.org/10.1542/peds.2007-3204 CrossRefPubMed

Park S-J, Sawitzki B, Kluwe L et al (2013) Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors. BMC Med 11:109. https://doi.org/10.1186/1741-7015-11-109 CrossRefPubMedPubMedCentral

Farschtschi S, Park S-J, Sawitzki B et al (2016) Effector T cell subclasses associate with tumor burden in neurofibromatosis type 1 patients. Cancer Immunol Immunother 65(9):1113–1121. https://doi.org/10.1007/s00262-016-1871-0 CrossRefPubMedPubMedCentral

Nishimura H, Honjo T (2001) PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 22(5):265–268CrossRefPubMed

10.

Turchinovich G, Ganter S, Bärenwaldt A et al (2018) NKp46 calibrates tumoricidal potential of type 1 innate lymphocytes by regulating TRAIL expression. J Immunol 200(11):3762–3768. https://doi.org/10.4049/jimmunol.1701333 CrossRefPubMed

11.

Gao Y, Souza-Fonseca-Guimaraes F, Bald T et al (2017) Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat Immunol 18(9):1004–1015. https://doi.org/10.1038/ni.3800 CrossRefPubMed

12.

Ribas A (2012) Tumor immunotherapy directed at PD-1. N Engl J Med 366(26):2517–2519. https://doi.org/10.1056/NEJMe1205943 CrossRefPubMed

13.

Lang D, Horner A, Brehm E et al (2019) Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study. Lung Cancer 134:59–65. https://doi.org/10.1016/j.lungcan.2019.05.033 CrossRefPubMed

14.

Wu X, Liu X, Koul S et al (2014) AXL kinase as a novel target for cancer therapy. Oncotarget 5(20):9546–9563. https://doi.org/10.18632/oncotarget.2542 CrossRefPubMedPubMedCentral

15.

Akslen LWR, Akslen LA, Watnick RS (eds) (2017) Biomarkers of the tumor microenvironment: basic studies and practical applications. Springer, Cham

16.

Johansson G, Peng P-C, Huang P-Y et al (2014) Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden. PLoS ONE 9(12):e115916. https://doi.org/10.1371/journal.pone.0115916 CrossRefPubMedPubMedCentral

17.

Kirkwood JM, Butterfield LH, Tarhini AA et al (2012) Immunotherapy of cancer in 2012. CA Cancer J Clin 62(5):309–335. https://doi.org/10.3322/caac.20132 CrossRefPubMedPubMedCentral

18.

Hong I-S (2016) Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types. Exp Mol Med 48(7):e242. https://doi.org/10.1038/emm.2016.64 CrossRefPubMedPubMedCentral

19.

Kalinski P (2012) Regulation of immune responses by prostaglandin E2. J Immunol 188(1):21–28. https://doi.org/10.4049/jimmunol.1101029 CrossRefPubMed

20.

Ferner RE, Gutmann DH (2013) Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol 115:939–955. https://doi.org/10.1016/B978-0-444-52902-2.00053-9 CrossRefPubMed

21.

Plotkin SR, Bredella MA, Cai W et al (2012) Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis. PLoS ONE 7(4):e35711. https://doi.org/10.1371/journal.pone.0035711 CrossRefPubMedPubMedCentral

22.

Mautner V-F, Asuagbor FA, Dombi E et al (2008) Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol 10(4):593–598. https://doi.org/10.1215/15228517-2008-011 CrossRefPubMedPubMedCentral

23.

Mallett G, Laurence A, Amarnath S (2019) Programmed cell death-1 receptor (PD-1)-mediated regulation of innate lymphoid cells. Int J Mol Sci 20(11):2836. https://doi.org/10.3390/ijms20112836 CrossRefPubMedCentral

24.

Salimi M, Wang R, Yao X et al (2018) Activated innate lymphoid cell populations accumulate in human tumour tissues. BMC Cancer 18(1):341. https://doi.org/10.1186/s12885-018-4262-4 CrossRefPubMedPubMedCentral

25.

Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. https://doi.org/10.1056/NEJMoa1305133 CrossRefPubMedPubMedCentral

26.

Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133. https://doi.org/10.1056/NEJMoa1302369 CrossRefPubMedPubMedCentral

27.

Edahiro R, Kanazu M, Kurebe H et al (2019) Clinical outcomes in non-small cell lung cancer patients with an ultra-high expression of programmed death ligand-1 treated using pembrolizumab as a first-line therapy: a retrospective multicenter cohort study in Japan. PLoS ONE 14(7):e0220570. https://doi.org/10.1371/journal.pone.0220570 CrossRefPubMedPubMedCentral

28.

Motzer RJ, Penkov K, Haanen J et al (2019) Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1103–1115. https://doi.org/10.1056/NEJMoa1816047 CrossRefPubMedPubMedCentral

29.

Sullivan RJ, Hamid O, Gonzalez R et al (2019) Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med 25(6):929–935. https://doi.org/10.1038/s41591-019-0474-7 CrossRefPubMed

30.

Antonia SJ (2019) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. Reply N Engl J Med 380(10):990. https://doi.org/10.1056/NEJMc1900407 CrossRefPubMed

31.

Davis LE, Nicholls LA, Babiker HM et al (2019) PD-1 inhibition achieves a complete metabolic response in a patient with malignant peripheral nerve sheath tumor. Cancer Immunol Res 7(9):1396–1400. https://doi.org/10.1158/2326-6066 CrossRefPubMed

32.

Huang W, Ran R, Shao B et al (2019) Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-019-05371-0 CrossRefPubMedPubMedCentral

33.

Mazel M, Jacot W, Pantel K et al (2015) Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol 9(9):1773–1782. https://doi.org/10.1016/j.molonc.2015.05.009 CrossRefPubMedPubMedCentral

34.

Nicolazzo C, Raimondi C, Mancini M et al (2016) Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab. Sci Rep 6:31726. https://doi.org/10.1038/srep31726 CrossRefPubMedPubMedCentral

35.

Oliveira-Costa JP, de Carvalho AF, da Silveira GG et al (2015) Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. Oncotarget 6(25):20902–20920. https://doi.org/10.18632/oncotarget.3939 CrossRefPubMedPubMedCentral

36.

Rekoske BT, Olson BM, McNeel DG (2016) Antitumor vaccination of prostate cancer patients elicits PD-1/PD-L1 regulated antigen-specific immune responses. Oncoimmunology 5(6):e1165377. https://doi.org/10.1080/2162402X.2016.1165377 CrossRefPubMedPubMedCentral

37.

Schehr JL, Schultz ZD, Warrick JW et al (2016) High specificity in circulating tumor cell identification is required for accurate evaluation of programmed death-ligand 1. PLoS ONE 11(7):e0159397. https://doi.org/10.1371/journal.pone.0159397 CrossRefPubMedPubMedCentral

38.

Satelli A, Batth IS, Brownlee Z et al (2016) Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci Rep 6:28910. https://doi.org/10.1038/srep28910 CrossRefPubMedPubMedCentral

39.

Bianchini M, Duchêne J, Santovito D et al (2019) PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function. Sci Immunol. https://doi.org/10.1126/sciimmunol.aar3054 CrossRefPubMed

40.

Shurell E, Singh AS, Crompton JG et al (2016) Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes. Oncotarget 7(39):64300–64308. https://doi.org/10.18632/oncotarget.11734 CrossRefPubMedPubMedCentral

41.

Haworth KB, Arnold MA, Pierson CR et al (2017) Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy. Oncotarget 8(47):82037–82048. https://doi.org/10.18632/oncotarget.18301 CrossRefPubMedPubMedCentral

42.

Taube JM (2014) Unleashing the immune system: PD-1 and PD-Ls in the pre-treatment tumor microenvironment and correlation with response to PD-1/PD-L1 blockade. Oncoimmunology 3(11):e963413. https://doi.org/10.4161/21624011.2014.963413 CrossRefPubMedPubMedCentral

Title: Upregulated immuno-modulator PD-L1 in malignant peripheral nerve sheath tumors provides a potential biomarker and a therapeutic target
Authors: Said Farschtschi
Lan Kluwe
Su-Jin Park
Su-Jun Oh
Nancy Mah
Victor-Felix Mautner
Andreas Kurtz
Publication date: 01-07-2020
Publisher: Springer Berlin Heidelberg
Keywords: Neurofibromatosis Type 1
Biomarkers
Published in: Cancer Immunology, Immunotherapy / Issue 7/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02548-1

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