Systemic soluble Programmed Death-Ligand 1 levels in sarcoidosis subjects does not vary with disease progression

Main Article Content

Binal Shah-Gandhi Ozioma S. Chioma Kenny A. Abel Erin M. Wilfong Wendi R. Mason Wonder P. Drake


Interaction of programmed cell death 1 (PD-1) receptor and its ligand 1 (PD-L1) is well studied in the field of fibrotic lung diseases, supporting its use as a biomarker of progression of interstitial lung disease. Anti PD-L1 therapy has shown effectiveness in improvement of many malignancies and murine models of autoimmune fibrotic lung diseases. Higher PD-1 expression on T cells and PD-L1 expression on human lung fibroblasts are known to contribute towards severity in sarcoidosis and idiopathic pulmonary fibrosis (IPF), respectively.  The focus of this investigation was to determine if soluble form of PD-L1 (sPD-L1) serves as predictive biomarker of disease severity in interstitial lung disease (ILD), such as scleroderma, sarcoidosis and IPF.  Comparison of local environments, such as bronchoalveolar lavage, revealed significantly higher sPD-L1 levels compared to systemic environments, such as peripheral blood (p=0.001, paired two-tailed Student’s t test).  Investigation of serum samples of healthy control, IPF, scleroderma and sarcoidosis patients reveal significantly higher levels in sarcoidosis and IPF patients, compared to patients with scleroderma (p=0.001; p=0.02, one-way ANOVA with Tukey’s respectively).   Comparison of serum levels between sarcoidosis patients and healthy controls revealed no significant differences (p=0.09, unpaired two-tailed t test).  In addition, comparison of physiologic parameters, such as percent predicated Forced Vital Capacity (FVC) and sPD-L1 levels in sarcoidosis and IPF patients revealed no correlation.   These observations suggest that sPD-L1 will not serve as a biomarker of sarcoidosis disease severity. Additional investigation of sPD-L1 in local environments is warranted.

Article Details

How to Cite
SHAH-GANDHI, Binal et al. Systemic soluble Programmed Death-Ligand 1 levels in sarcoidosis subjects does not vary with disease progression. Medical Research Archives, [S.l.], v. 9, n. 9, sep. 2021. ISSN 2375-1924. Available at: <>. Date accessed: 25 oct. 2021. doi:
Research Articles


1. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi:10.1146/annurev.immunol.26.021607.090331
2. Dai S, Jia R, Zhang X, Fang Q, Huang L. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol. Jul 2014;290(1):72-9. doi:10.1016/j.cellimm.2014.05.006
3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. Feb 2002;2(2):116-26. doi:10.1038/nri727
4. Zheng Z, Bu Z, Liu X, et al. Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications. Chin J Cancer Res. Feb 2014;26(1):104-11. doi:10.3978/j.issn.1000-9604.2014.02.08
5. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. Apr 15 2007;109(8):1499-505. doi:10.1002/cncr.22588
6. Hamanishi J, Mandai M, Iwasaki M, 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 U S A. Feb 27 2007;104(9):3360-5. doi:10.1073/pnas.0611533104
7. Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. Apr 1 2010;116(7):1757-66. doi:10.1002/cncr.24899
8. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. Jul 1 2013;19(13):3462-73. doi:10.1158/1078-0432.CCR-13-0855
9. Wong RM, Scotland RR, Lau RL, et al. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. Oct 2007;19(10):1223-34. doi:10.1093/intimm/dxm091
10. Wang W, Lau R, Yu D, Zhu W, Korman A, Weber J. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol. Sep 2009;21(9):1065-77. doi:10.1093/intimm/dxp072
11. Karunarathne DS, Horne-Debets JM, Huang JX, et al. Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4(+) T Cell Immunity. Immunity. Aug 16 2016;45(2):333-45. doi:10.1016/j.immuni.2016.07.017
12. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. Jun 28 2012;366(26):2443-54. doi:10.1056/NEJMoa1200690
13. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. Nov 27 2014;515(7528):558-62. doi:10.1038/nature13904
14. Zhu X, Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget. Nov 14 2017;8(57):97671-97682. doi:10.18632/oncotarget.18311
15. Sorensen SF, Demuth C, Weber B, Sorensen BS, Meldgaard P. Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib. Lung Cancer. Oct 2016;100:77-84. doi:10.1016/j.lungcan.2016.08.001
16. Okuma Y, Hosomi Y, Nakahara Y, Watanabe K, Sagawa Y, Homma S. High plasma levels of soluble programmed cell death ligand 1 are prognostic for reduced survival in advanced lung cancer. Lung Cancer. Feb 2017;104:1-6. doi:10.1016/j.lungcan.2016.11.023
17. Wang L, Wang H, Chen H, et al. Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. Oncotarget. Dec 1 2015;6(38):41228-36. doi:10.18632/oncotarget.5682
18. Frigola X, Inman BA, Lohse CM, et al. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. Apr 1 2011;17(7):1915-23. doi:10.1158/1078-0432.CCR-10-0250
19. Liu S, Zhu Y, Zhang C, et al. The Clinical Significance of Soluble Programmed Cell Death-Ligand 1 (sPD-L1) in Patients With Gliomas. Front Oncol. 2020;10:9. doi:10.3389/fonc.2020.00009
20. Zhang Q, Vignali DA. Co-stimulatory and Co-inhibitory Pathways in Autoimmunity. Immunity. May 17 2016;44(5):1034-51. doi:10.1016/j.immuni.2016.04.017
21. Chen F, Li S, Wang T, Shi J, Wang G. Clinical Heterogeneity of Interstitial Lung Disease in Polymyositis and Dermatomyositis Patients With or Without Specific Autoantibodies. Am J Med Sci. Jan 2018;355(1):48-53. doi:10.1016/j.amjms.2017.07.013
22. Vukmirovic M, Herazo-Maya JD, Blackmon J, et al. Identification and validation of differentially expressed transcripts by RNA-sequencing of formalin-fixed, paraffin-embedded (FFPE) lung tissue from patients with Idiopathic Pulmonary Fibrosis. BMC Pulm Med. Jan 12 2017;17(1):15. doi:10.1186/s12890-016-0356-4
23. Cassius C, Le Buanec H, Bouaziz JD, Amode R. Biomarkers in Adult Dermatomyositis: Tools to Help the Diagnosis and Predict the Clinical Outcome. J Immunol Res. 2019;2019:9141420. doi:10.1155/2019/9141420
24. Geng Y, Liu X, Liang J, et al. PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis. JCI Insight. Mar 21 2019;4(6)doi:10.1172/jci.insight.125326
25. Braun NA, Celada LJ, Herazo-Maya JD, et al. Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity. Am J Respir Crit Care Med. Sep 1 2014;190(5):560-71. doi:10.1164/rccm.201401-0188OC
26. Ni K, Liu M, Zheng J, et al. PD-1/PD-L1 Pathway Mediates the Alleviation of Pulmonary Fibrosis by Human Mesenchymal Stem Cells in Humanized Mice. Am J Respir Cell Mol Biol. Jun 2018;58(6):684-695. doi:10.1165/rcmb.2017-0326OC
27. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis. Sep 1999;16(2):149-73.
28. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. Sep 1 2018;198(5):e44-e68. doi:10.1164/rccm.201807-1255ST
29. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. Nov 2013;65(11):2737-47. doi:10.1002/art.38098
30. Celada LJ, Kropski JA, Herazo-Maya JD, et al. PD-1 up-regulation on CD4(+) T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-beta1 production. Sci Transl Med. Sep 26 2018;10(460)doi:10.1126/scitranslmed.aar8356
31. Liu H, Patel D, Welch AM, et al. Association Between Occupational Exposures and Sarcoidosis: An Analysis From Death Certificates in the United States, 1988-1999. Chest. Aug 2016;150(2):289-98. doi:10.1016/j.chest.2016.01.020
32. Swigris JJ, Olson AL, Huie TJ, et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med. Jun 1 2011;183(11):1524-30. doi:10.1164/rccm.201010-1679OC