Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press77910.17650/2313-805X-2025-12-4-73-80REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИReview ArticleAlternative signaling pathways for regulation of programmed cell death 1 protein expression in T lymphocytesАльтернативные пути регуляции экспрессии рецептора программируемой гибели клеток 1 в Т-лимфоцитахhttps://orcid.org/0000-0003-2902-9336BatorovE. V.БаторовЕ. В.
Russian Federation
ebatorov@mail.ruhttps://orcid.org/0009-0000-1100-9826VasilchenkoP. V.ВасильченкоП. В.
Russian Federation
p.vasilchenko@g.nsu.ruhttps://orcid.org/0000-0003-2346-6279ChernykhE. R.ЧерныхЕ. Р.
Russian Federation
ebatorov@mail.ruResearch Institute of Fundamental and Clinical ImmunologyФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии»14122025124738020062025Copyright ©; 2025, Batorov E.V., Vasilchenko P.V., Chernykh E.R.Copyright ©; 2025, Баторов Е.В., Васильченко П.В., Черных Е.Р.2025Batorov E.V., Vasilchenko P.V., Chernykh E.R.Баторов Е.В., Васильченко П.В., Черных Е.Р.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/779

Programmed cell death protein 1 (PD-1), an inhibitory checkpoint receptor, is the target of anti-PD-1 monoclonal antibodies that are effectively used in the treatment of various malignancies. The goal of anti-PD-1 therapy is to prevent a state of T cell exhaustion that occurs as a result of ongoing stimulation via the T-cell receptor and is characterized by T cell dysfunction and surface expression of PD-1 and other checkpoint receptors. However, antigen-independent stimulation of lymphocytes by cytokines acting through the JAK/STAT signaling pathways can also up-regulate inhibitory checkpoint receptor expression. PI3K/Akt/mTOR and Ras/MEK/ERK signaling pathways regulate the proliferation, activation and metabolism of T cells and appear to indirectly influence the expression of checkpoint molecules. The consequences of blocking non-exhausted T cells with targeted therapies are currently not studied. The publication examines the main signaling pathways of PD-1 expression in T cells.

Белок программируемой гибели клеток 1 (programmed cell death protein 1, PD-1) – ингибиторный чек-поинт-рецептор – является мишенью для анти-PD-1-моноклональных антител, эффективно используемых в терапии многих опухолей. Цель анти-PD-1-терапии – предотвращение дисфункции Т-лимфоцитов, возникающей вследствие продолжающейся стимуляции через Т-клеточный рецептор и характеризующейся снижением пролиферативной, цитотоксической и цитокин-продуцирующей активности и экспрессией PD-1, а также и других чек-поинт-рецепторов. Однако антигеннезависимая стимуляция лимфоцитов цитокинами, действующая через сигнальные пути JAK/STAT, также может привести к экспрессии на них данной группы молекул. По-видимому, опосредованно на экспрессию чек-поинт-молекул могут влиять сигнальные пути PI3K/Akt/mTOR и Ras/MЕK/ERK, регулирующие пролиферацию, активацию и метаболизм Т-клеток. Последствия блокады таргетными препаратами неистощенных Т-клеток в настоящее время не изучены. В публикации рассмотрены основные сигнальные пути экспрессии ингибиторных чек-поинт-рецепторов PD-1 в Т-клетках.

programmed cell death 1PD-1Т cell exhaustionhomeostatic proliferationNFATSTAT5STAT3рецептор программируемой клеточной гибели 1PD-1Т-клеточное истощениегомеостатическая пролиферацияNFATSTAT5STAT3Российский научный фондRussian Science Foundation20-75-10132-ПРоссийский научный фонд, проект № 20-75-10132-П.Gellrich F.F., Schmitz M., Beissert S., Meier F. Anti-PD-1 and novel combinations in the treatment of melanoma – an update. J Clin Med 2020;9(1):223. DOI: 10.3390/jcm9010223Fitzsimmons T.S., Singh N., Walker T.D.J. et al. Immune checkpoint inhibitors efficacy across solid cancers and the utility of PD-L1 as a biomarker of response: a systematic review and meta-analysis. Front Med (Lausanne) 2023;10:1192762. DOI: 10.3389/fmed.2023.1192762Dai S., Jia R., Zhang X. et al. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol 2014;290(1):72–9. DOI: 10.1016/j.cellimm.2014.05.006Hamanishi 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-zArasanz H., Gato-Cañas M., Zuazo M. et al. PD1 signal transduction pathways in T cells. Oncotarget 2017;8(31):51936–45. DOI: 10.18632/oncotarget.17232.Chamoto K., Yaguchi T., Tajima M., Honjo T. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1. Nat Rev Immunol 2023;23(10):682–95. DOI: 10.1038/s41577-023-00867-9Bardhan K., Anagnostou T., Boussiotis V.A. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol 2016;7:550. DOI: 10.3389/fimmu.2016.00550Lee J.U., Kim L.K., Choi J.M. Revisiting the concept of targeting NFAT to control t cell immunity and autoimmune diseases. Front Immunol 2018;9:2747. DOI: 10.3389/fimmu.2018.02747Simon S., Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 2017;7(1):e1364828. DOI: 10.1080/2162402X.2017.1364828Jenkins E., Whitehead T., Fellermeyer M. et al. The current state and future of T-cell exhaustion research. Oxf Open Immunol 2023;4(1):iqad006. DOI: 10.1093/oxfimm/iqad006Martinez G.J., Pereira R.M., Äijö T. et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 2015;42(2):265–78. DOI: 10.1016/j.immuni.2015.01.006Sekine T., Perez-Potti A., Nguyen S. et al. TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Sci Immunol 2020;5(49):eaba7918. DOI: 10.1126/sciimmunol.aba7918Franco F., Jaccard A., Romero P. et al. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2020;2(10):1001–12. DOI: 10.1038/s42255-020-00280-9Van der Leun A.M., Thommen D.S., Schumacher T.N. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer 2020;20(4):218–32. DOI: 10.1038/s41568-019-0235-4ElTanbouly M.A., Noelle R.J. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat Rev Immunol 2021;21(4):257–67. DOI: 10.1038/s41577-020-00454-2Lowther D.E., Goods B.A., Lucca L.E. et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 2016;1(5):e85935. DOI: 10.1172/jci.insight.85935Batorov E.V., Ineshina A.D., Aristova T.A. et al. PD-1+ and TIM-3+ T cells widely express common γ-chain cytokine receptors in multiple myeloma patients, and IL-2, IL-7, IL-15 stimulation up-regulates PD-1 and TIM-3 on T cells. Oncol Res 2024;32(10):1575–87. DOI: 10.32604/or.2024.047893Kinter A.L., Godbout E.J., McNally J.P. et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008;181(10):6738–46. DOI: 10.4049/jimmunol.181.10.6738Mujib S., Jones R.B., Lo C. et al. Antigen-independent induction of Tim-3 expression on human T cells by the common г-chain cytokines IL-2, IL-7, IL-15, and IL-21 is associated with proliferation and is dependent on the phosphoinositide 3-kinase pathway. J Immunol 2012;188(8):3745–56. DOI: 10.4049/jimmunol.1102609Marshall N., Hutchinson K., Marron T.U. et al. Antitumor T-cell homeostatic activation is uncoupled from homeostatic inhibition by checkpoint blockade. Cancer Discov 2019;9(11):1520–37. DOI: 10.1158/2159-8290.CD-19-0391Batorov E.V., Aristova T.A., Pronkina N.V. et al. Highly proliferative and functional PD-1+ and TIM-3+ T cells are transiently increased in multiple myeloma following autologous hematopoietic stem cell transplantation. Int Immunopharmacol 2021;100:108093. DOI: 10.1016/j.intimp.2021.108093Wang G., Tajima M., Honjo T., Ohta A. STAT5 interferes with PD-1 transcriptional activation and affects CD8+ T-cell sensitivity to PD-1-dependent immunoregulation. Int Immunol 2021;33(11):563–72. DOI: 10.1093/intimm/dxab059Beltra J.C., Abdel-Hakeem M.S., Manne S. et al. Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure. Immunity 2023;56(12):2699–718:e11. DOI: 10.1016/j.immuni.2023.11.005Beltra J.C., Bourbonnais S., Bédard N. et al. IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection. Proc Natl Acad Sci USA 2016;113(37):E5444–53. DOI: 10.1073/pnas.1604256113Liu Y., Zhou N., Zhou L. et al. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol 2021;22(3):358–69. DOI: 10.1038/s41590-020-00850-9Moses C.T., Thorstenson K.M., Jameson S.C., Khoruts A. Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells. Proc Natl Acad Sci USA 2003;100(3):1185–90. DOI: 10.1073/pnas.0334572100Hickman S.P., Turka L.A. Homeostatic T cell proliferation as a barrier to T cell tolerance. Philos Trans R Soc Lond B Biol Sci 2005;360(1461):1713–21. DOI: 10.1098/rstb.2005.1699Lin S.J., Chen A.T., Welsh R.M. Immune system derived from homeostatic proliferation generates normal CD8 T-cell memory but altered repertoires and diminished heterologous immune responses. Blood 2008;112(3):680–9. DOI: 10.1182/blood-2008-01-132464Onyshchenko K., Luo R., Guffart E. et al. Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice. Nat Commun 2023;14(1):2087. DOI: 10.1038/s41467-023-37825-xMuhammad S., Fan T., Hai Y. et al. Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies. Mol Cancer 2023;22(1):121. DOI: 10.1186/s12943-023-01826-7Oh H.M., Yu C.R., Golestaneh N. et al. STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors. J Biol Chem 2011;286(35):30888–97. DOI: 10.1074/jbc.M111.253500Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol 2021;39:51–76. DOI: 10.1146/annurev-immunol-061020-053702Sun Q., Zhao X., Li R. et al. STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection. J Exp Med 2023;220(4):e20220686. DOI: 10.1084/jem.20220686Kaminskiy Y., Melenhorst J.J. STAT3 role in T-cell memory formation. Int J Mol Sci 2022;23(5):2878. DOI: 10.3390/ijms23052878Powell M.D., Lu P., Neeld D.K. et al. IL-6/STAT3 signaling axis enhances and prolongs pdcd1 expression in murine CD8 T cells. Immunohorizons 2022;6(12):872–82. DOI: 10.4049/immunohorizons.2100112Hanna B.S., Llaó-Cid L., Iskar M. et al. Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity. Immunity 2021;54(12):2825–41.e10. DOI: 10.1016/j.immuni.2021.11.004Dong Y., Chen J., Chen Y., Liu S. Targeting the STAT3 oncogenic pathway: cancer immunotherapy and drug repurposing. Biomed Pharmacother 2023;167:115513. DOI: 10.1016/j.biopha.2023.115513Zou S., Tong Q., Liu B. et al. Targeting STAT3 in cancer immunotherapy. Mol Cancer 2020;19(1):145. DOI: 10.1186/s12943-020-01258-7Chen Y., Xu Z., Sun H. et al. Regulation of CD8+ T memory and exhaustion by the mTOR signals. Cell Mol Immunol 2023;20(9):1023–39. DOI: 10.1038/s41423-023-01064-3Bishop E.L., Gudgeon N., Dimeloe S. Control of T cell metabolism by cytokines and hormones. Front Immunol 2021;12:653605. DOI: 10.3389/fimmu.2021.653605El Hage A., Dormond O. Combining mTOR inhibitors and t cell-based immunotherapies in cancer treatment. Cancers (Basel) 2021;13(6):1359. DOI: 10.3390/cancers13061359Damasio M.P., Marchingo J.M., Spinelli L. et al. Extracellular signal-regulated kinase (ERK) pathway control of CD8+ T cell differentiation. Biochem J 2021;478(1):79–98. DOI: 10.1042/BCJ20200661Xiao X., Shi J., He C. et al. ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy. Nat Commun 2023;14(1):2859. DOI: 10.1038/s41467-023-38605-3Wang X., Tao X., Chen P. et al. MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB. Signal Transduct Target Ther 2024;9(1):293. DOI: 10.1038/s41392-024-01986-y