N.Yu. Sokolov1, D.V. Rogozhin2, K.A. Borzov3, O.V. Kovaleva4, I.N. Kuznetsov5, A.K. Valiev6, P.L. Prishchep7, I.S. Stilidi8, N.E. Kushlinskii9
1,5,9 Russian University of Medicine Ministry of Health of the Russian Federation (Moscow, Russia)
1 S.P. Botkin Moscow Multidisciplinary Scientific and Clinical Center named after (Moscow, Russia)
2-4,6-9 N.N. Blokhin National Medical Research Center of Oncology Ministry of Health of the Russian Federation (Moscow, Russia)
1 strivp@mail.ru, 2 pathol.777@mail.ru, 3 kirill_borzov@bk.ru, 4 ovkovaleva@gmail.com, 5 npkredo@yandex.ru, 6 dsion@rambler.ru, 7 paulig92@mail.ru, 8 ronc@list.ru, 9 kne3108@gmail.com
The role of sPD-L1 and sPD-1 as prognostic or predictive markers in various malignancies is the subject of intense debate. Although their functional significance remains unclear, increasing evidence suggests that sPD-L1 and sPD-1 may play an important role in shaping immune responses and affect therapeutic outcomes and prognosis of cancer. The aim of the work is to analyze the content of sPD-1 and sPD-L1 in the blood serum of patients with bone tumors, taking into account the main clinical and morphological characteristics of the disease. Results. It was shown that sPD-1 and sPD-L1 were detected in the overwhelming majority of healthy individuals and patients with bone tumors. The median concentration of sPD-L1 in patients with bone tumors was 2.5 times higher than in the control, and the concentrations of the sPD-1 receptor in the group of patients and controls did not differ. It was found that the levels of sPD-L1 in the blood serum of patients with malignant (MCT), borderline (BCT), benign bone tumors (BBT) did not differ, but were significantly higher than in the control. In the control and in the group of patients with MBT, no correlation was established between the levels of sPD-1 and sPD-L1. The analysis of variance did not reveal any relationship between the levels of sPD-1, sPD-L1 in the blood serum in the control and examined groups of patients, taking into account the gender of the examined patients, but it established a significant decrease in sPD-1 concentrations in the control and in patients with ZOK. In patients with ZOK, no relationship was found between sPD-1 and sPD-L1 and the T and M indices; the analysis with the N index was not performed due to the small number of observations. Reliable differences in sPD-1 concentrations depending on the histological structure of bone sarcoma were established. The lowest median sPD-1 concentration was found in chondrosarcoma, and the highest in Ewing's tumor. At the same time, multivariate analysis showed that age determined sPD-1 levels in the blood of patients with BTS to a greater extent (p=0.015) than the morphological variant of the tumor (p=0.049). Concentrations of sPD-L1 in the blood of patients with MOC did not reflect the morphological variant of the tumor. Also, significantly low concentrations of sPD-1 were found in G2 tumors and a significant decrease in sPD-L1 concentrations as the degree of differentiation of MOC decreased. No relationship was found between the level of sPD-1, sPD-L1 in the blood of patients with MOC and different localization of the tumor in the bones of the skeleton and the type of affected bone (tubular, spongy). The lowest median sPD-1 was found in the blood of patients with pubic bone sarcoma and, on the contrary, the highest in femoral bone sarcoma. The study of soluble forms of PD-1 and PD-L1 in the blood of patients with bone tumors is at the beginning of the path, and the preliminary data obtained by us and other authors allow us to think about the prospects of this work. First of all, this is due to the fact that new molecules have been identified that participate in the progression of bone tumors and can also serve as targets for immunotherapy, the mechanisms of which need to be studied in more depth in the dynamics of the tumor process in patients. In addition, the obtained data suggest a possible role of the above-mentioned immune molecules for more effective combined therapy with already known drugs. Recently, the first positive results of such combined treatment options have appeared in the literature, including bone sarcomas.
Sokolov N.Yu., Rogozhin D.V., Borzov K.A., Kovaleva O.V., Kuznetsov I.N., Valiev A.K., Prishchep P.L., Stilidi I.S., Kushlinskii N.E. Soluble forms of PD-1 and PD-L1 in patients with bone tumors. Technologies of Living Systems. 2025. V. 22. № 2. Р. 17-28. DOI: https://doi.org/10.18127/j20700997-202502-02 (In Russian).
- Wojtukiewicz M.Z., Rek M.M., Karpowicz K. et al. Inhibitors of immune checkpoints – PD-1, PD-L1, CTLA-4 – New opportunities for cancer patients and a new challenge for internists and general practitioners. Cancer Metastasis Rev. 2021. V. 40. № 3. P. 949–982. DOI: 10.1007/s10555-021-09976-0
- Festino L., Botti G., Lorigan P. et al. Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection? Drugs. 2016. V. 76. № 9. P. 925–945. DOI: 10.1007/s40265-016-0588-x
- Zheng D., Hou X., Yu J., He X. Combinatorial Strategies with PD-1/PD-L1 Immune Checkpoint Blockade for Breast Cancer Therapy: Mechanisms and Clinical Outcomes. Front. Pharmacol. 2022. V. 13: 928369. DOI: 10.3389/fphar.2022.928369
- Xin Yu J., Hubbard-Lucey V.M., Tang J. Immuno-oncology drug development goes global. Nat. Rev. Drug Discov. 2019. V. 18. № 12. P. 899–900. DOI: 10.1038/d41573-019-00167-9
- Sharpe A.H., Wherry E.J., Ahmed R., Freeman G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 2007. V. 8. № 3. P. 239–245. DOI: 10.1038/ni1443
- Torabi A., Amaya C.N., Wians F.H. Jr., Bryan B.A. PD-1 and PD-L1 expression in bone and soft tissue sarcomas. Pathology. 2017. V. 49. № 5. P. 506–513. DOI: 10.1016/j.pathol.2017.05.003
- Han Y., Liu D., Li L. PD-1/PD-L1 pathway: Current researches in cancer. Am. J. Cancer Res. 2020. V. 10. № 3. P. 727–742.
- Nagato T., Ohkuri T., Ohara K. et al. Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy. Cancer Immunol. Immunother. 2017. V. 66. № 7. P. 877–890. DOI: 10.1007/s00262-017-1987-x
- Kushlinskij N.E., Gershtejn E.S., Goryacheva I.O. i dr. Rastvorimye formy receptora kontrol'noj tochki immuniteta PD-1 i ego liganda PD-L1 v syvorotke krovi bol'nyh pochechno-kletochnym rakom: kliniko-morfologicheskie korrelyacii. Onkourologiya. 2019. V. 15. № 1. S. 15-22. DOI: 10.17650/1726-9776-2019-15-1-15-22 (in Russian).
- Zhu X., Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget. 2017. V. 8. № 57. P. 97671–97682. DOI: 10.18632/oncotarget.18311
- Wei W., Xu B., Wang Y. et al. Prognostic significance of circulating soluble programmed death ligand-1 in patients with solid tumors: A meta-analysis. Medicine (Baltimore). 2018. V. 97. № 3. Article e9617. DOI: 10.1097/MD.0000000000009617
- Naberezhnov D.S., Morozov A.A., Fridman M.V. i dr. Sistema PD-1/PD-L1 pri immunoterapii raka pochki. CHast' 1. Signal'nyj put' PD-1/PD-L1, ego rol' v immunnoj sisteme i immunoterapii. Medicinskij alfavit. 2018. T. 2. № 29. S. 22–31. (in Russian).
- Bailly C., Thuru X., Quesnel B. Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases. Cancers. 2021. V. 13. № 12. Article 3034. DOI: 10.3390/cancers13123034
- Kushlinskij N.E., Alferov A.A., Bulycheva I.V. i dr. Sravnitel'nyj analiz urovnej rastvorimyh form receptora i liganda kontrol'noj tochki immuniteta PD-1/PD-L1 v syvorotke krovi bol'nyh tipichnymi osteosarkomoj i hondrosarkomoj kosti. Klinicheskaya laboratornaya diagnostika. 2020. T. 65. № 11. S. 669–675. DOI: 10.18821/0869-2084-2020-65-11-669-675 (in Russian).
- Alferov A.A., Efimova M.M., Kuz'min YU.B. i dr. Klyuchevye kontrol'nye tochki immuniteta i ih ingibitory v terapii opuholej kostej. Chast' 1. Signal'naya sistema belka programmiruemoj kletochnoj gibeli PD-1/PD-L. Tekhnologii zhivyh sistem. 2021. T. 18. № 1. S. 5–17. DOI: 10.18127/j20700997-202101-01 (in Russian).
- Abu Hejleh T., Furqan M., Ballas Z., Clamon G. The clinical significance of soluble PD-1 and PD-L1 in lung cancer. Crit. Rev. Oncol./Hematol. 2019. V. 143. P. 148–152. DOI: 10.1016/j.critrevonc.2019.08.009
- Khan M., Zhao Z., Arooj S. et al. Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy. Front. Immunol. 2020. V. 11. Article 587460. DOI: 10.3389/fimmu.2020.587460
- Kushlinskii N.E., Kovaleva O.V., Gratchev A.N. et al. Assessing the Clinical Relevance of Soluble PD-1 and PD-L1: A Multi-Cohort Study Across Diverse Tumor Types and Prognostic Implications. Biomedicines. 2025. V. 13. № 2. 500. DOI: 10.3390/ biomedicines13020500
- Gershtejn E.S., Kuz'min YU.B., Alferov A.A. i dr. Sravnitel'noe issledovanie rastvorimyh form belkov kontrol'nyh tochek immuniteta VISTA, PD-1, PD-L1 i regulyatora kostnogo gomeostaza RANKL u bol'nyh opuholyami kostej. Molekulyarnaya medicina. 2022. T. 20. № 6. S. 25–32. DOI: 10.29296/24999490-2022-06-04 (in Russian).

