E.S. Gershtein – Dr. Sc. (Biol.), Professor, Leading Research Scientist, Clinical Biochemistry Laboratory, 

N.N. Blokhin National Medical Research Center of Oncology (Moscow)

D.N. Kushlinsky – Ph.D. (Med.), Senior Research Scientist, Department of Radiation and Combined Treatment of Gynecological Diseases, Medical Radiological Scientific Center n.a. A.F. Tsyba – Branch of the Federal State

Budgetary Institution «National Medical Center of Radiology» of the Ministry of Health  of Russian Federation (Moscow)

I.V. Tereshkina – Ph.D. (Med.), Clinical Biochemistry Laboratory, N.N. Blokhin National Medical Research  Center of Oncology (Moscow)

D.O. Utkin – Surgeon, Department of Oncogynecology, Moscow City Oncological Hospital № 62» (Moscow)

N.E. Kushlinskii – Dr.Sc. (Med.), Professor, Academician of RAS, Heard of Clinical Biochemistry Laboratory, N.N. Blokhin National Medical Research Center of Oncology (Moscow)

Ovarian cancer is one of the most common malignant tumors of the female reproductive system; it is characterized by an extremely aggressive clinical course, is often detected at advanced stages, and in certain cases is resistant to chemotherapy. Currently, attempts to apply anti-PD-1/PD-L1 immunotherapy for the treatment of ovarian cancer are being made taking into consideration PD-1 and PD-L1 expression on the tumor cells and tumor infiltrating lymphocytes (TILs) and other immune cells as possible markers of the sensitivity to such drugs. However, the data on the predictive efficiency of these markers are ambiguous. Measurement of their soluble forms – sPD-1 and sPD-L1 – in the peripheral blood may help to overcome at least some problems of immunohistochemical (IHC) testing.

Aim of the review – to analyze the clinical significance of the programmed cell death-1 protein PD-1 and its ligand PD-L1 investigation in ovarian cancer patients.

The investigations of the role of PD-1 receptor and its ligand PD-L1 expression in the tumors and tumor infiltrating immune cells in ovarian cancer accumulated in recent 5-7 years are varied in methodical approaches and design, and discordant in results. According to some authors, tumor PD-1 and/or PD-L1 expression positively correlated with peritoneal dissemination of ovarian cancer suppressing the activity of cytotoxic T lymphocytes; increased PD-L1 expression in high-grade tumors was also demonstrated in a number of investigations. Meanwhile, the data on the prognostic significance of tumor PD-L1 and PD-1 in ovarian cancer are even more controversial. Several studies demonstrated that the level of PD-L1 and PD-1 proteins’ expression on tumor cells, the density of PD-1+ and PD-L1+ TILs, as well as high level of PD-1+ and PD-L1 mRNA were favorable prognostic factors for progression-free survival. Others have revealed the longest overall survival in HGSOC patients with PD-L1 negative tumor cells and intensive tumor infiltration by CD8+ lymphocytes, and the shortest – in those with inverse combination of these parameters. Association of PD-1 and/or PD-L1 expression with the presence of BRCA1/2 and TP53 gene mutations and microsatellite instability (one of the markers of sensitivity to anti-PD-1/PD-L1 treatment) was also demonstrated. Univariate regression analysis revealed rs2227982 C>T and rs4143815 C>G polymorphisms of PD-1 gene as well as PD1/PD-L1 expression to be prognostic factors for ovarian cancer, but only advanced FIGO stage and low PD-1/PD-L1 expression remained unfavorable prognosticators in multivariate analysis. A variety of investigations demonstrated PD-1 and PD-L1 expression on TILs and tumor infiltrating macrophages controversially affecting patients’ survival and the effect of therapy. Several studies of sPD-L1 in blood plasma of ovarian cancer patients were published recently indicating to its possible value as a marker for prediction and monitoring of anti-PD-1/PD-L1 immunotherapy efficiency. 

PD-1/PD-L signaling system controlling antitumor T cell immunity endures significant changes and apparently plays an important role in ovarian cancer development and progression. Promising results of anti-PD-1/PD-L1 therapy of ovarian cancer resistant to traditional platinum-containing regimens confer the importance of the study of the expression of the components of this pathway on tumor and immune cells, as well as of the soluble forms of the receptor and the ligand circulating in the peripheral blood. The main goal of such studies is the evaluation of the possibilities of implication of these markers for the prediction and monitoring of the efficiency of such immunotherapy. 

Gershtein E.S., Kushlinsky D.N., Tereshkina I.V., Utkin D.O., Kushlinskii N.E. Clinical implication of the programmed cell DEATH-1 protein PD-1 and ITS ligand PD-L1 in ovarian cancer (review). Technologies of living systems. 2020. V. 17. № 3. P. 5–15. DOI: 10.18127/j20700997-202003-01 (In Russian).

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