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Molecular Medicine Peer-reviewed scientific journal

Molecular Medicine

ОБЗОР2025, No. 1

NEW DIAGNOSTIC BIOMARKERS FOR EARLY STAGES OF CUTANEOUS T-CELL LYMPHOMA

Gafurova O.A., Danilik O.N., Anufrieva O.V., Syrovatskaya Ya.V., Orobets M.A., Artykova R.A., Gosteeva E.A., Rudenko E.E., Smolyannikova V.A.

Authors and affiliations

O.A. Gafurova, O.N. Danilik, O.V. Anufrieva, Ya.V. Syrovatskaya,
M.A. Orobets, R.A. Artykova, E.A. Gosteeva, E.E. Rudenko, V.A. Smolyannikova
Federal State Autonomous Educational Institution of Higher Education I.M.Sechenov First Moscow State Medical University
of the Ministry of Health of the Russian Federation (Sechenov University), st. Trubetskaya, 8/2, Moscow, 119048, Russian Federation

Pages
27–33
Published
2025
Section
ОБЗОР
Молекулярная медицина, 2025, № 1Issue2025, No. 1Go to the issue →
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Abstract

Currently, the diagnosis of early stages of cutaneous T-cell lymphomas (CTCL) is one of the most challenging tasks in dermatology. This review is devoted to the analysis of new immunohistochemical (IHC) markers that could be considered diagnostic for the detection of CTCL, as well as potential targets for targeted therapy of the disease.
The aim of this review was to determine and summarize new promising biomarkers that are not currently used for the diagnosis of early stages of CTCL.
Material and methods: the analysis and systematization of scientific literature over the past 5 years was carried out in the PubMed database using the search algorithm: “cutaneous T-cell lymphoma” AND (“immunohistochem” OR “IHC” OR “expression”).
Results. All found biomarkers were divided into 3 groups:
• Tumor progression markers: OX40 и OX40L, ICOS, TOX, GATA-3, TSP-1, CD47, YKL-40, IKZF2, E-FABP, CXCR4, CD69, HSPA1A, ZFP36, TXNIP and IL7R;
• Differential diagnostic markers: STAT4, YKL-40, BCL11B, CD70, hBD-2 and psoriasin;
• Tumor microenvironment markers: IL-10, PD-L1, FAP-α, CD69, granzyme B, NKp46, TIM3, CD57 and LAG3.
Conclusion. The most promising marker to diagnose the early stages is YKL-40 since it can serve as both a prognostic and differential diagnostic marker.

Keywords

Authors and affiliations

O.A. Gafurova, O.N. Danilik, O.V. Anufrieva, Ya.V. Syrovatskaya,
M.A. Orobets, R.A. Artykova, E.A. Gosteeva, E.E. Rudenko, V.A. Smolyannikova
Federal State Autonomous Educational Institution of Higher Education I.M.Sechenov First Moscow State Medical University
of the Ministry of Health of the Russian Federation (Sechenov University), st. Trubetskaya, 8/2, Moscow, 119048, Russian Federation

References

Dobos G., Miladi M., Michel L., Ram-Wolff C., Battistella M., Bagot M. et al. Recent advances on cutaneous lymphoma epidemiology. La Presse Médicale. 2022; 51 (1): 104108. https://doi.org/10.1016/j.lpm.2022.104108

. Демина О.М., Акилов О.Е., Румянцев А.Г. Т-клеточные лимфомы кожи: современные данные патогенеза, клиники и терапии. Онкогематология. 2018; 13 (3): 25–38. https://doi.org/10.17650/1818-8346-2018-13-3-25-38. [Demina O.M., Akilov O.E., Rumyantsev A.G. Cutaneous T-cell lymphomas: modern data of pathogenesis, clinics and therapy. Onkogematologiâ. 2018; 13 (3): 25–38 (in Russian)]

Kawai H., Ando K., Maruyama D., Yamamoto K., Kiyohara E., Terui Y., Fukuhara N. et al. Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. Cancer Science. 2021; 112 (6): 2426–35. https://doi.org/10.1111/cas.14906

Поддубная И.В., Савченко В.В. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. ООО Буки Веди, 2016. [Poddubnaya I.V., Savchenko V.V. Rossijskie klinicheskie rekomendacii po diagnostike i lecheniyu limfoproliferativnyh zabolevanij. OOO Buki Vedi, 2016 (in Russian)]

Geller S., Hollmann T.J., Horwitz S.M., Myskowski P.L., Pulitzer M. C-C chemokine receptor 4 expression in CD8+ cutaneous T-cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment. Histopathology. 2020; 76 (2): 222–32. https://doi.org/10.1111/his.13960

Olisova O.Y., Grekova E.V., Varshavsky V.A., Gorenkova L.G., Alekseeva E.A., Zaletaev D.V., Sydikov A.A. Current possibilities of the differential diagnosis of plaque parapsoriasis and the early stages of mycosis fungoides. Arkh Patol. 2019; 81 (1): 9–17. https://doi.org/10.17116/patol2019810119

Xu B., Liu F., Gao Y., Sun J., Li Y., Lin Y., Liu X. et al. High Expression of IKZF2 in Malignant T Cells Promotes Disease Progression in Cutaneous T Cell Lymphoma. Acta Derm Venereol. 2021; 101 (12): adv00613. https://doi.org/10.2340%2Factadv.v101.570

Yang C., Mai H., Peng J., Zhou B., Hou J., Jiang D. STAT4: an immunoregulator contributing to diverse human diseases. Int. J. Biol. Sci. 2020; 16 (9): 1575–85. https://doi.org/10.7150%2Fijbs.41852

Sun S., Dong H., Yan T., Li J., Liu B., Shao P., Li J., Liang C. Role of TSP-1 as prognostic marker in various cancers: a systematic review and meta-analysis. BMC Med Genet. 2020; 21 (1): 139. https://doi.org/10.1186/s12881-020-01073-3

Tizaoui K., Yang J.W., Lee K.H., Kim J.H., Kim M., Yoon S., Jung Y. et al. The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review. Int. J. Biol. Sci. 2022; 18 (9): 3731–46. https://doi.org/10.7150/ijbs.67587

Chang M.C., Chiang P.F., Kuo Y.J., Peng C.L., Chen I.C., Huang C.Y., Chen C.A., Chiang Y.C. Develop companion radiopharmaceutical YKL40 antibodies as potential theranostic agents for epithelial ovarian cancer. Biomed Pharmacother. 2022; 155: 113668. https://doi.org/10.7150%2Fjca.62285

Andtbacka R.H.I., Wang Y., Pierce R.H., Campbell J.S., Yushak M., Milhem M., Ross M. еt al. Mavorixafor, an Orally Bioavailable CXCR4 Antagonist, Increases Immune Cell Infiltration and Inflammatory Status of Tumor Microenvironment in Patients with Melanoma. Cancer Res Commun. 2022; 2 (8): 904–13. https://doi.org/10.1158/2767-9764.crc-22-0090

13. Zhang Y., Luo Y., Qin S.L., Mu Y.F., Qi Y., Yu M.H., Zhong M. The clinical impact of ICOS signal in colorectal cancer patients. Oncoimmunology. 2016; 5 (5): e1141857. https://doi.org/10.1080/2162402x.2016.1141857

Xu-Monette Z.Y., Zhou J., Young K.H. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018; 131 (1): 68–83. https://doi.org/10.1182/blood-2017-07-740993

Wang L., Rocas D., Dalle S., Sako N., Pelletier L., Martin N., Dupuy A. еt al. Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype: an integrative clinical, pathological and molecular case series study. Br. J. Dermatol. 2022; 187 (6): 970–80. https://doi.org/10.1111/bjd.21791

Karpathiou G., Papoudou-Bai A., Ferrand E., Dumollard J.M., Peoc’h M. STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. Pathol Res Pract. 2021; 223: 153477. https://doi.org/10.1016/j.prp.2021.153477

Zhang Y., Zhang Y., Gu W., Sun B. TH1/TH2 cell differentiation and molecular signals. Adv Exp. Med. Biol. 2014; 841: 15–44. https://doi.org/10.1007/978-94-017-9487-9_2

Murga-Zamalloa C., Wilcox R.A. GATA-3 in T-cell lymphoproliferative disorders. IUBMB Life. 2020; 72 (1): 170–7. https://doi.org/10.1002%2Fiub.2130

Tindemans I., Serafini N., Di Santo J.P., Hendriks R.W. GATA-3 function in innate and adaptive immunity. Immunity. 2014; 41 (2): 191–206. https://doi.org/10.1016/j.immuni.2014.06.006

Hetemäki I., Kaustio M., Kinnunen M., Heikkilä N., Keskitalo S., Nowlan K., Miettinen S. et al. Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells. Sci Immunol. 2021; 6 (65): eabe3454. https://doi.org/10.1126/sciimmunol.abe3454

Ouyang W., O’Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019; 50 (4): 871–91. https://doi.org/10.1016/j.immuni.2019.03.020

Hayat S.M.G., Bianconi V., Pirro M., Jaafari M.R., Hatamipour M., Sahebkar A. CD47: role in the immune system and application to cancer therapy. Cell Oncol (Dordr). 2020; 43 (1): 19–30. https://doi.org/10.1007/s13402-019-00469-5

Chakraborty S., Kubatzky K.F., Mitra D.K. An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis. Int. J. Mol. Sci. 2019; 20 (9): 2113. https://doi.org/10.3390/ijms20092113

Matusiewicz K., Iwańczak B., Matusiewicz M. Th9 lymphocytes and functions of interleukin 9 with the focus on IBD pathology. Adv Med. Sci. 2018; 63 (2): 278–84. https://doi.org/10.1016/j.advms.2018.03.002

Cibrián D., Sánchez-Madrid F. CD69: from activation marker to metabolic gatekeeper. Eur. J. Immunol. 2017; 47 (6): 946–53. https://doi.org/10.1002/eji.201646837

Gorabi A.M., Hajighasemi S., Kiaie N., Gheibi Hayat S.M., Jamialahmadi T., Johnston T.P., Sahebkar A. The pivotal role of CD69 in autoimmunity. J. Autoimmun. 2020; 111: 102453. https://doi.org/10.1016/j.jaut.2020.102453

Moar P., Tandon R. Galectin-9 as a biomarker of disease severity. Cell Immunol. 2021; 361: 104287. https://doi.org/10.1016/j.cellimm.2021.104287

Suzuki H., Boki H., Kamijo H., Nakajima R., Oka T., Shishido-Takahashi N. et al. YKL-40 Promotes Proliferation of Cutaneous T-Cell Lymphoma Tumor Cells through Extracellular Signal-Regulated Kinase Pathways. J. Invest Dermatol. 2020; 140 (4): 860–868.e3. https://doi.org/10.1016/j.jid.2019.09.007

Kawana Y., Suga H., Kamijo H., Miyagaki T., Sugaya M., Sato S. Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome. Int. J. Mol. Sci. 2021; 22 (22): 12576. https://doi.org/10.3390/ijms222212576

Di Raimondo C., Rubio-Gonzalez B., Palmer J., Weisenburger D.D., Zain J., Wu X., Han Z. et al. Expression of immune checkpoint molecules programmed death protein 1, programmed death-ligand 1 and inducible T-cell co-stimulator in mycosis fungoides and Sézary syndrome: association with disease stage and clinical outcome. Br. J. Dermatol. 2022; 187 (2): 234–43. https://doi.org/10.1111/bjd.21063

Atwa H.A., Abdelrahman D.I. The Value of Immunohistochemical Expression of TOX, ICOS, and GATA-3 in the Diagnosis of Mycosis Fungoides. Appl Immunohistochem Mol Morphol. 2023; 31 (3): 163–71. https://doi.org/10.1097/pai.0000000000001110

Kamijo H., Miyagaki T., Takahashi-Shishido N., Nakajima R., Oka T., Suga H., Sugaya M., Sato S. Thrombospondin-1 promotes tumor progression in cutaneous T-cell lymphoma via CD47. Leukemia. 2020; 34 (3): 845–56. https://doi.org/10.1038/s41375-019-0622-6

Takahashi-Shishido N., Sugaya M., Morimura S., Suga H., Oka T., Kamijo H., Miyagaki T., Sato S. Mycosis fungoides and Sézary syndrome tumor cells express epidermal fatty acid-binding protein, whose expression decreases with loss of epidermotropism. J. Dermatol. 2021; 48 (5): 685–9. https://doi.org/10.1111/1346-8138.15775

Rindler K., Jonak C., Alkon N., Thaler F.M., Kurz H., Shaw L.E., Stingl G. et al. Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma. Mol Cancer. 2021; 20 (1): 124. https://doi.org/10.1186/s12943-021-01419-2

Liu J., Zheng X., Pang X., Li L., Wang J., Yang C., Du G. Ganglioside GD3 synthase (GD3S), a novel cancer drug target. Acta Pharm Sin B. 2018; 8 (5): 713–20. https://doi.org/10.1016%2Fj.apsb.2018.07.009

Lennon M.J., Jones S.P., Lovelace M.D., Guillemin G.J., Brew B.J. Bcl11b-A Critical Neurodevelopmental Transcription Factor-Roles in Health and Disease. Front Cell Neurosci. 2017; 11: 89. https://doi.org/10.3389%2Ffncel.2017.00089

Wajant H. Therapeutic targeting of CD70 and CD27. Expert Opin Ther Targets. 2016; 20 (8): 959–73. https://doi.org/10.1517/14728222.2016.1158812

. Sans-de San Nicolàs L., Czarnowicki T., Akdis M., Pujol R.M., Lozano-Ojalvo D., Leung D.Y.M., Guttman-Yassky E., Santamaria-Babi L.F. CLA+ memory T cells in atopic dermatitis. Allergy. 2023. https://doi.org/10.1111/all.15816

Cieślik M., Bagińska N., Górski A., Jończyk-Matysiak E. Human β-Defensin 2 and Its Postulated Role in Modulation of the Immune Response. Cells. 2021; 10 (11): 2991. https://doi.org/10.3390/cells10112991

. Pan M., Zhang F., Qu K., Liu C., Zhang J. TXNIP: A Double-Edged Sword in Disease and Therapeutic Outlook. Oxid Med Cell Longev. 2022; 2022: 7805115. https://doi.org/10.1155%2F2022%2F7805115

Fang H., Khoury J.D., Torres-Cabala C.A., Ng S.B., Xu J., El Hussein S., Hu S. et al. Expression pattern and diagnostic utility of BCL11B in mature T- and NK-cell neoplasms. Pathology. 2022; 54 (7): 893–9. https://doi.org/10.1016/j.pathol.2022.04.012

Wu C.H., Wang L., Yang C.Y., Wen K.W., Hinds B., Gill R., McCormick F. et al. Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models. Blood Adv. 2022; 6 (7): 2290–302. https://doi.org/10.1182/bloodadvances.2021005714

Wehkamp U., Jost M., Wehkamp K., Harder J. Dysregulated Expression of Antimicrobial Peptides in Skin Lesions of Patients with Cutaneous T-cell Lymphoma. Acta Derm Venereol. 2020; 100 (1): adv00017. https://doi.org/10.2340/00015555-3372

Peru S., Prochazkova-Carlotti M., Cherrier F., Velazquez J., Richard E., Idrissi Y., Cappellen D. et al. Cutaneous Lymphocyte Antigen Is a Potential Therapeutic Target in Cutaneous T-Cell Lymphoma. J. Invest Dermatol. 2022; 142 (12): 3243–3252.e10. https://doi.org/10.1016/j.jid.2022.06.016

Zheng Y., Fang Y.C., Li J. PD-L1 expression levels on tumor cells affect their immunosuppressive activity. Oncol Lett. 2019; 18 (5): 5399–407. https://doi.org/10.3892/ol.2019.10903

Mori N., Jin J., Krishnamachary B., Mironchik Y., Wildes F., Vesuna F., Barnett J.D., Bhujwalla Z.M. Functional roles of FAP-α in metabolism, migration and invasion of human cancer cells. 2023. https://doi.org/10.3389/fonc.2023.1068405

Mehdi S.J., Moerman-Herzog A., Wong H.K. Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma. BMC Cancer. 2021; 21 (1): 492. https://doi.org/10.1186/s12885-021-08142-7

Scheffschick A., Nenonen J., Xiang M., Winther A.H., Ehrström M., Wahren-Herlenius M. et al. Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor. Front Immunol. 2023; 14: 1168684. https://doi.org/10.3389/fimmu.2023.1168684

Wu X., Hsu D.K., Wang K.H., Huang Y., Mendoza L., Zhou Y., Hwang S.T. IL-10 is overexpressed in human cutaneous T-cell lymphoma and is required for maximal tumor growth in a mouse model. Leuk Lymphoma. 2019; 60 (5): 1244–52. https://doi.org/10.1080/10428194.2018.1516037

How to cite

Gafurova O.A., Danilik O.N., Anufrieva O.V., Syrovatskaya Ya.V., Orobets M.A., Artykova R.A., Gosteeva E.A., Rudenko E.E., Smolyannikova V.A. (2025). NEW DIAGNOSTIC BIOMARKERS FOR EARLY STAGES OF CUTANEOUS T-CELL LYMPHOMA. Molecular Medicine, 23(1), 27–33. https://doi.org/10.29296/24999490-2025-01-03

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