sPD-1/sPD-L1 proteins in non-small cell lung cancer and esophageal squamous cell carcinoma

Background. Implementation of immunotherapy in clinical oncological practice has significantly improved the results of cancer treatment. It resulted in the need for seeking new markers to assess the effectiveness of therapy and the disease prognosis.

Aim. To analyze the content of soluble forms of PD-1 and PD-L1 immune checkpoint proteins in the blood serum of patients with non-small cell lung cancer and esophageal squamous cell carcinoma and their association with clinical and morphological characteristics of the disease and the disease prognosis.

Materials and methods. The study included tumor samples obtained from 43 patients with non-small cell lung cancer and 21 patients with esophageal squamous cell carcinoma. The concentration of sPD-L1 and sPD-1 in the blood serum was determined using enzyme-linked immunosorbent assay (ELISA). The Mann – Whitney test was used to determine statistically significant differences in independent groups. A correlation analysis was performed using the Spearman’s rank correlation coefficient. Overall survival was analyzed by constructing survival curves using the Kaplan – Meier method and a Cox proportional hazards model. The differences were considered statistically significant at p < 0.05.

Results. The study showed that sPD-1 and sPD-L1 were found in the blood serum of both cancer patients and healthy donors, and their concentrations did not differ significantly. It was shown that the high concentration of sPD-L1 in the blood serum of patients with non-small cell lung cancer was significantly associated with the late stage of the disease and was an independent unfavorable prognostic factor. It should be noted that for patients with esophageal cancer, an unfavorable prognostic marker was the high concentration of the soluble form of PD-1 protein, and not PD-L1 ligand, as in case of lung cancer.

Conclusion. The content of sPD-1 and sPD-L1 in the blood serum can have different prognostic significance for various types of cancer, and further studies are required to confirm their clinical usability.

1. Orme J.J., Enninga E.A.L., Lucien-Matteoni F., Dale H., Burgstaler E., Harrington S.M. et al. Therapeutic plasma exchange clears circulating soluble PD-L1 and PD-L1-positive extracellular vesicles. J. Immunother Cancer. 2020;8(2):e001113. DOI: 10.1136/jitc-2020-001113.

2. Chen Y., Wang Q., Shi B., Xu P., Hu Z., Bai L. et al. Development 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):23–28. DOI: 10.1016/j.cyto.2011.06.004.

3. Daassi D., Mahoney K.M., Freeman G.J. The importance of exosomal PDL1 in tumour immune evasion. Nat. Rev. Immunol. 2020;20(4):209–215. DOI: 10.1038/s41577-019-0264-y.

4. Zhou J., Mahoney K.M., Giobbie-Hurder A., Zhao F., Lee S., Liao X. et al. Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade. Cancer Immunol. Res. 2017;5(6):480–492. DOI: 10.1158/2326-6066.CIR-160329.

5. Hofman P., Heeke S., Alix-Panabieres C., Pantel K. Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients? Ann. Oncol. 2019;30(9):1448–1459. DOI: 10.1093/annonc/mdz196.

6. Кушлинский Н.Е., Герштейн Е.С., Горячева И.О. и др. Растворимые формы рецептора контрольной точки иммунитета PD-1 и его лиганда PD-L1 в сыворотке крови больных почечно-клеточным раком: клинико-морфологические корреляции. Онкоурология. 2019;15(1):15–22. DOI: 10.17650/1726-9776-2019-15-1-15-22.

7. Ковалева О.В., Рашидова М.А., Грачев А.Н., Масленников В.В., Булычева И.В., Герштейн Е.С. и др. Факторы иммуносупрессии PD-1, PD-L1, IDO1 и колоректальный рак. Доклады Российской академии наук. Науки о жизни. 2021;497(1):160–164. DOI: 10.31857/S2686738921020153.

8. Ji S., Chen H., Yang K., Zhang G., Mao B., Hu Y. et al. Peripheral cytokine levels as predictive biomarkers of bene fit from immune checkpoint inhibitors in cancer therapy. Biomed. Рharmacother. 2020;129:110457. DOI: 10.1016/j.biopha.2020.110457.

9. Assi H.I., Kamphorst A.O., Moukalled N.M., Ramalingam S.S. Immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer. 2018;124(2):248–261. DOI: 10.1002/cncr.31105

10. Costantini A., Julie C., Dumenil C., Helias-Rodzewicz Z., Tisserand J., Dumoulin J. et al. Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab. Oncoimmunology. 2018;7(8):e1452581. DOI: 10.1080/2162402X.2018.1452581.

11. 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. 2017;104:1–6. DOI: 10.1016/j.lungcan.2016.11.023.

12. Castello A., Rossi S., Toschi L., Mansi L., Lopci E. Soluble PD-L1 in NSCLC Patients Treated with Checkpoint Inhibitors and Its Correlation with Metabolic Parameters. Cancers (Basel). 2020;12(6):1373. DOI: 10.3390/cancers12061373

13. Jovanovic D., Roksandic-Milenkovic M., Kotur-Stevulje vic J., Ceriman V., Vukanic I., Samardzic N. et al. Soluble sPD-L1 and serum amyloid A1 as potential biomarkers for lung cancer. J. Med. Biochem. 2019;38(3):332–341. DOI: 10.2478/jomb-2018-0036.

14. Jia Y., Li X., Zhao C., Ren S., Su C., Gao G. et al. Soluble PDL1 as a predictor of the response to EGFR-TKIs in non-small cell lung cancer patients with EGFR mutations. Front. Oncol. 2020;10:1455. DOI: 10.3389/fonc.2020.01455.

15. Sorensen S.F., Demuth C., Weber B., Sorensen B.S., 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. 2016;100:77–84. DOI: 10.1016/j.lungcan.2016.08.001.

16. Shiraishi T., Toyozumi T., Sakata H., Murakami K., Kano M., Matsumoto Y. et al. Soluble PD-L1 concentration is proportional to the expression of PD-L1 in tissue and is associated with a poor prognosis in esophageal squamous cell carcinoma. Oncology. 2022;100(1):39–47. DOI: 10.1159/000518740.

17. Fu R., Jing C.Q., Li X.R., Tan Z.F., Li H.J. Prognostic significance of serum PD-L1 level in patients with locally advanced or metastatic esophageal squamous cell carcinoma treated with combination cytotoxic chemotherapy. Cancer Manag. Res. 2021;13:4935–4946. DOI: 10.2147/CMAR.S312690.