Soluble forms of the immune check-point receptor PD-1 and its ligand PD-L1 in blood serum of patients with renal cell carcinoma: clinical and pathologic correlations

Background.Renal cancer is one of the most immunosensitive oncologic diseases. A prominent breakthrough in this field was gained with the development of medications directed to the suppression of PD-1/PD-L immune check-point signaling pathway that in normal physiologic conditions controls autoimmune reactions. Tumor PD-1 and/or PD-L1 expression is investigated both as a predictor of corresponding immunotherapy efficiency, and as molecular markers of overall prognosis and patients’ survival. This goal could be also attained by the measure­ment of soluble forms of these proteins (sPD-1 иsPD-L1) in blood serum.

Objective of the study— comparative evaluation ofsPD-1 and sPD-L1 content in blood serum of practically healthy persons and patients with renal cancer and benign kidney tumors; analysis of the associations between these markers and clinical and pathologic characteristics of renal cancer.

Materials and methods. 106 renal cancer (64 male and 42 female; age 33—81 years) and 11 patients with benign kidney tumors (3 male and 8 female; age 29—84 years) were included in the study. Control group comprised 19 men and 18 women of matching age. 57patients had stage I, 12 — II, 15 — III and 22 — stage IVrenal cancer. Serum sPD-L1 and sPD-1 concentrations were measured using standard enzyme immunoassay kits (Affimetrix, eBioscience, USA).

Results. sPD-L1 levels in blood serum of patients with primary renal cancer and benign tumors were significantly higher than in control (p <0.0001 and p <0.05 respectively). sPD-L1 level significantly increased with disease stage (p <0.001), with T index increase from 1 to 3 declining at T4, was significantly higher in patients with lymph node metastases (both N1, and N2) than in those without such lesions (N0); it was also increased in М+ patients, and in patients with grade III—IVin comparison to grade I—II tumors. sPD-1 levels did not differ sig­nificantly between study groups, did not depend on disease stage, presence of lymph node or distant metastases, but were decreased in patients with Т4 as compared to those with less advanced primary tumor, and were significantly lower in patients with clear-cell than in those with chromophobic or papillary histologic variants.

Conclusion. Serum sPD-L1 in renal cancer patients correlates with disease progression and tumor grade, and can be regarded as promising marker for monitoring of anti-PD1/PD-L1 treatment efficiency. Potential clinical implications of sPD-1 require further investigations and analysis.

1. Ainsworth N.L., Lee J.S., Eisen T. Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. Expert Rev Anticancer Ther 2009;9(12):1793—805.DOI: 10.1586/era.09.144.PMID: 19954291.

2. Bracarda S., Porta C., Boni C. et al. Could interferon still play a role in metastatic renal cell carcinoma? A randomized study of two schedules of sorafenib plus interferonalpha 2a (RAPSODY). Eur Urol 2013;63(2):254—61. DOI: 10.1016/j.eururo.2012.08.027. PMID: 22964169.

3. Procopio G., Verzoni E., Bracarda S. et al. Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial. Ann Oncol 2013;24(12):2967—71. DOI: 10.1093/annonc/mdt375. PMID: 24063860.

4. Kushlinskii N.E., Fridman M.V., Morozov A.A. et al. Modern approaches to kid¬ney cancer immunotherapy. Cancer Urology 2018;14(2):54—67. (In Russ.).

5. Hamanishi J., Mandai M., Matsumura N. et al. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol 2016;21(3):462—73. DOI: 10.1007/s10147-016-0959-z. PMID: 26899259.

6. Massari F., Santoni M., Ciccarese C. et al. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev 2015;41(2):114—21. DOI: 10.1016/j.ctrv.2014.12.013. PMID: 25586601.

7. Sacher A.G., Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol 2016;2(9):1217—22. DOI: 10.1001/jamaoncol.2016.0639. PMID: 27310809.

8. Tsang J.Y., Au W.L., Lo K.Y. et al. PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients. Breast Cancer Res Treat 2017;162(1):19—30. DOI: 10.1007/s10549-016-4095-2. PMID: 28058578.

9. Wang Y., Lin J., Cui J. et al. Prognostic value and clinicopathological features of PD-1/PD-L1 expression with mismatch repair status and desmoplastic stroma in Chinese patients with pancreatic cancer. Oncotarget 2017;8(6):9354-65. DOI: 10.18632/oncotarget.14069. PMID: 28030840.

10. Zhu X., Lang J. The significance and therapeutic potential of PD-1 and its ligands in ovarian cancer: A systematic review. Gynecol Oncol 2016;142(1):184—9. DOI: 10.1016/j.ygyno.2016.04.002. PMID: 27063803.

11. Kim K.S., Sekar R.R., Patil D. et al. Evaluation of programmed cell death protein 1 (PD-1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma. Oncoimmunology 2018;7(4):e1413519. DOI: 10.1080/2162402X.2017.1413519. PMID: 29632730.

12. Erlmeier F., Weichert W., Schrader A.J. et al. Prognostic impact of PD-1 and its ligands in renal cell carcinoma. Med Oncol 2017;34(6):99. DOI: 10.1007/s12032-017-0961-y. PMID: 28432616.

13. Yuasa T., Masuda H., Yamamoto S. et al. Biomarkers to predict prognosis and response to checkpoint inhibitors. Int J Clin Oncol 2017;22(4):629-34. DOI: 10.1007/s10147-017-1122-1. PMID: 28382562.

14. Topalian S.L., Taube J.M., Anders R.A. et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016;16(5):275—87. DOI: 10.1038/nrc.2016.36. PMID: 27079802.

15. Yun S., Vincelette N.D., Green M.R. et al. Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials. Cancer Med 2016;5(7):1481-91. DOI: 10.1002/cam4.732. PMID: 27167347.

16. Zhu X., Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget 2017;8(57):97671—82. DOI: 10.18632/oncotarget.18311. PMID: 29228642.

17. Ding Y., Sun C., Li J. et al. The prognostic significance of soluble programmed death ligand 1 expression in cancers: a systematic review and meta-analysis. Scand J Immunol 2017;86(5):361—7. DOI: 10.1111/sji.12596. PMID: 28930374.

18. Theodoraki M.N., Yerneni S.S., Hoff¬mann T.K. et al. Clinical significance of PD-L1(+) exosomes in plasma of head and neck cancer patients. Clin Cancer Res 2018;24(4):896—905. DOI: 10.1158/1078-0432.CCR-17-2664. PMID: 29233903.

19. Guo X., Wang J., Jin J. et al. High serum level of soluble programmed death ligand 1 is associated with a poor prognosis in Hodgkin lymphoma. Transl Oncol 2018;11(3):779—85. DOI: 10.1016/j.tranon.2018.03.012. PMID: 29698935.

20. Kim H.J., Park S., Kim K.J. et al. Clinical significance of soluble programmed cell death ligand-1 (sPD-L1) in hepatocellular carcinoma patients treated with radiotherapy. Radiother Oncol 2018;129(1):130—5. DOI: 10.1016/j.radonc.2017.11.027. PMID: 19954291.

21. Huang X., Zhang W., Zhang Z. et al. Prog¬nostic value of programmed cell death 1 ligand-1 (PD-L1) or PD-1 expression in patients with osteosarcoma: a metaanalysis. J Cancer 2018;9(14):2525-31. DOI: 10.7150/jca.25011. PMID: 30026851.

22. Moch H., Humphrey P.A., Ulbright T.M., Reuter V.E. WHO classification of tumours of the urinary system and male genital organs. IARC, Lyon, 2016.

23. Chen Y., Wang Q., Shi B. et al. Develop¬ment of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine 2011;56(2):231—8. DOI: 10.1016/j.cyto.2011.06.004. PMID: 21733718.

24. Frigola X., Inman B.A., Lohse C.M. 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 2011;17(7):1915—23. DOI: 10.1158/1078-0432.CCR-10-0250. PMID: 21355078.