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PD-1^(+)and TIM-3^(+)T cells widely express commonγ-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

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Oncology research 2024年第10期32卷 1575-1587页

作者： EGOr V.BATOrOV ALISA D.INESHINA TATIANA A.ArISTOVA VErA V.DENISOVA SVETLANA A.SIZIKOVA DArIA S.BATOrOVA GALINA Y.USHAKOVA EKATErINA Y.SHEVELA elena r.chernykh Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical ImmunologyNovosibirsk630099Russia V.Zelman Institute of Medicine and Psychology Novosibirsk National Research State UniversityNovosibirsk630090Russia Department of Hematology and Bone Marrow Transplantation Research Institute of Fundamental and Clinical ImmunologyNovosibirsk630099Russia

Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)***,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic *** aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint ***:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM ***:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and *** of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−*** proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription ***,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 *** stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in ***:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine *** in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell *** blockade appears to alleviate lymphopenia-induced prolif

关键词： Autologous hematopoietic stem cell transplantation(AHSCT) CD25 CD122 Eomesodermin(EOMES) Homeostatic proliferation

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Antitumor efficacy of multi-target in situ vaccinations with CpG oligodeoxynucleotides,anti-OX40,anti-PD1 antibodies,and aptamers

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The Journal of Biomedical research 2023年第3期37卷 194-212页

作者： Anastasia S.Proskurina Vera S.ruzanova Genrikh S.ritter Yaroslav r.Efremov Zakhar S.Mustafin Sergey A.Lashin Ekaterina A.Burakova Alesya A.Fokina Timofei S.Zatsepin Dmitry A.Stetsenko Olga Y.Leplina Alexandr A.Ostanin elena r.chernykh Sergey S.Bogachev Institute of Cytology and Genetics Siberian Branch of the Russian Academy of SciencesNovosibirsk 630090Russia Department of Natural Sciences Novosibirsk State UniversityNovosibirsk 630090Russia Department of Physics Novosibirsk State UniversityNovosibirsk 630090Russia Department of Chemistry Moscow State UniversityMoscow 119991Russia research Institute of Fundamental and Clinical Immunology Novosibirsk630099Russia

To overcome immune tolerance to cancer,the immune system needs to be exposed to a multi-target action ***,we investigated the activating effect of CpG oligodeoxynucleotides(ODNs),mesyl phosphoramidate CpG ODNs,anti-OX40 antibodies,and OX40 rNA aptamers on major populations of immunocompetent cells ex *** analysis of the antitumor effects of in situ vaccination with CpG ODNs and anti-OX40 antibodies,as well as several other combinations,such as mesyl phosphoramidate CpG ODNs and OX40 rNA aptamers,was *** against programmed death 1(PD1)checkpoint inhibitors or their corresponding PD1 DNA aptamers were also added to vaccination regimens for analytical *** scenarios were considered:a weakly immunogenic Krebs-2 carcinoma grafted in CBA mice;a moderately immunogenic Lewis carcinoma grafted in C57Black/6 mice;and an immunogenic A20 B cell lymphoma or an Ehrlich carcinoma grafted in BALB/c *** anti-PD1 antibodies(CpG+αOX40+αPD1)to in situ vaccinations boosts the antitumor *** to be used instead of antibodies,aptamers also possess antitumor activity,although this effect was less *** strongest effect across all the tumors was observed in highly immunogenic A20 B cell lymphoma and Ehrlich carcinoma.

关键词： immunogenicity Krebs-2 carcinoma Lewis carcinoma Ehrlich carcinoma A20 B cell lymphoma mesyl phosphoramidate

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Efficacy of the new therapeutic approach in curing malignant neoplasms on the model of human glioblastoma

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Cancer Biology & Medicine 2021年第3期18卷 910-930页

作者： Evgeniya V.Dolgova Oleg M.Andrushkevich Polina E.Kisaretova Anastasia S.Proskurina Genrikh S.ritter Tatyana D.Dubatolova Margarita V.romanenko Oleg S.Taranov Yaroslav r.Efremov Evgeniy L.Zavyalov Alexandr V.romaschenko Sergey V.Mishinov Svetlana S.Kirikovich Evgeniy V.Levites Ekaterina A.Potter Alexandr A.Ostanin elena r.chernykh Stanislav Yu.roshchin Anatoliy V.Bervitskiy Galina I.Moysak Jamil A.rzaev Sergey S.Bogachev Institute of Cytology and Genetics SB rAS Novosibirsk 630090Russia A.I.Evdokimov Moscow State University of Medicine and Dentistry Moscow 127473Russia Institute of Molecular and Cellular Biology Novosibirsk 630090Russia Novosibirsk State University Novosibirsk 630090Russia The State research Center of Virology and Biotechnology"Vector" KoltsovoNovosibirsk 630559Russia First Department of Neurosurgery Ya.L.Tsivian Novosibirsk Research Institute of Traumatology and OrthopaedicsNovosibirsk 630091Russia Institute of Fundamental and Clinical immunology Novosibirsk 630099Russia Sklifosovsky research Institute of Emergency Medicine Moscow 129010Russia Federal Center of Neurosurgery Novosibirsk 630048Russia

Objective:Glioma is a highly invasive tumor,frequently disposed in essential areas of the brain,which makes its surgical excision extremely difficult;meanwhile adjuvant therapy remains quite ***:In the current report,a new therapeutic approach in curing malignant neoplasms has been performed on the U87 human glioblastoma *** approach,termed"Karanahan",is aimed at the eradication of cancer stem cells(CSCs),which were recently shown to be capable of internalizing fragments of extracellular double-stranded *** being internalized,these fragments interfere in the process of repairing interstrand cross-links caused by exposure to appropriate cytostatics,and such an interference results either in elimination of CSCs or in the loss of their tumorigenic *** of the approach requires a scheduled administration of cytostatic and complex composite double-stranded DNA ***:U87 cells treated in vitro in accordance with the Karanahan approach completely lost their tumorigenicity and produced no grafts upon intracerebral transplantation into immunodeficient *** SCID mice with developed subcutaneous grafts,the treatment resulted in reliable slowing down of tumor growth rate(Priment with intracerebral transplantation of U87 cells followed by surgical excision of the developed graft and subsequent therapeutic treatment,the Karanahan approach was shown to reliably slow down the tumor growth rate and increase the median survival of the mice twofold relative to the ***:The effectiveness of the Karanahan approach has been demonstrated both in vitro and in vivo in treating developed subcutaneous grafts as well as orthotopic grafts after surgical excision of the tumor.

关键词： Glioblastoma U87 cell line mytomycin C cancer stem cells TAMrA

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Genes associated with testicular germ cell tumors and testicular dysgenesis in patients with testicular microlithiasis

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Asian Journal of Andrology 2018年第6期20卷 593-599页

作者： Ilya S Dantsev Evgeniy V Ivkin Aleksey A Tryakin Dmitriy N Godlevski Oleg Yu Latyshev Victoriya V rudenko Dmitry S Mikhaylenko Vyacheslav B chernykh elena A Volodko Aleksey B Okulov Oleg B Loran Marina V Nemtsova russian Medical Academy ef Postgraduate Education Moscow 123995Russia N.N.Blokhin russian Cancer research Center Moscow 115478Russia research Centre of Medical Genetics Moscow 115478Russia M.Sechenov First Moscow State Medical University Moscow 119991Russia N.I.Pirogov russian National research Medical University Moscow 117997Russia.

Testicular microlithiasis （TM） is one of the symptoms of testicular dysgenesis syndrome （TDS）. TM is particularly interesting as an informative marker of testicular germ cell tumors （TGCTs）. KIT ligand gene （KITLG）, BCL2 antagonist/killer 1 （BAK1）, and sprouty rTK signaling antagonist 4 （SPrY4） genes are associated with a high risk of TGCTs, whereas bone morphogenetic protein 7 gene （BMP7）, transforming growth factor beta receptor 3 gene （TGFBr3）, and homeobox D cluster genes （HOXD） are related to TDS. Using polymerase chain reaction-restriction fragment length polymorphism （PCr-rFLP） analysis, we investigated allele and genotype frequencies for KITLG （rs995030, rs1508595）, SPrY4 （rs4624820, rs6897876）, BAK1 （rs210138）, BMP7 （rs388286）, TGFBr3 （rs12082710）, and HOXD （rs17198432） in 142 TGCT patients, 137 TM patients, and 153 fertile men （control group）. We found significant differences in the KITLG GG_rs995030 genotype in TM （P= 0.01） and TGCT patients （P = 0.0005） compared with the control. We also revealed strong associations between KITLGrs1508595 and TM （G allele, P = 0.003; GG genotype, P= 0.01） and between KITLG_rs1508595 and TGCTs （G allele, P-- 0.0001; GG genotype, P = 0.0007）. Moreover, there was a significant difference in BMP7_rs388286 between the TGCT group and the control （T allele, P = 0.00004; TT genotype, P = 0.00006） and between the TM group and the control （T allele, P= 0.04）. HOXDalso demonstrated a strong association with TGCTs （rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001）. Furthermore, significant differences were found between the TGCT group and the control in the BAK1_rs210138 G allele （P= 0.03） and the GG genotype （P= 0.01）. KITLG and BMP7genes, associated with the development of TGCTs, may also be related to TM. In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development.

关键词： associations genotype high risk testicular dysgenesis syndrome testicular microlithiasis

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