medalphabetМедицинский алфавитMedical alphabet2078-56312949-2807ООО «Альфмед»10.33667/2078-5631-2021-31-13-18medalphabet-2311Research ArticleСтатьиАктивация лимфоцитов in vitro для иммунотерапии больных меланомойActivation of lymphocytes in vitro for immunotherapy of patients with melanomahttps://orcid.org/0000-0002-3881-3221АбакушинаЕ. В.AbakushinaE. V.

Абакушина Елена Вячеславовна, д.м.н., с.н.с. лаборатории клинической иммунологии1; проф. кафедры радионуклидной медицины отдела биотехнологий2

г. Обнинск

Scopus: 15844847700

WosResearcher: O‑6947–2014

еLibrary: 594958

Abakushina Elena V., DM Sci (habil.), senior researcher of Laboratory of Clinical Immunology1; prof. at Dept of Radionuclide Medicine, Dept of Biotechnology2

Obninsk

Scopus: 15844847700

WosResearcher: O‑6947–2014

eLibrary: 594958

 

akushina@mail.ruhttps://orcid.org/0000-0001-8673-3616ГельмЮ. В.Gel’mYu. V.

Гельм Юлия Витальевна, н.с. лаборатории клинической иммунологии

г. Обнинск

Scopus: 57190795044.

WosResearcher: O‑7325–2014.

еLibrary: 751187

 

Gel’m Yulia V., researcher of Laboratory of Clinical Immunology

Obninsk

Scopus: 57190795044

WosResearcher: O‑7325–2014

eLibrary: 751187

Julia_marizina@mail.ruhttps://orcid.org/0000-0002-4879-7958ЛысюкЕ. Ю.LyssukE. Yu.

Лысюк Елена Юрьевна, к.б.н., с.н.с. лаборатории молекулярной иммунологии

Scopus: 22135546600

WosResearcher: G‑2951–2017

еLibrary: 96321

Москва

Lysyuk Elena Yu., PhD Bio Sci, senior researcher of Laboratory of Molecular Immunology

Moscow

Scopus: 22135546600

WosResearcher: G‑2951–2017

eLibrary: 96321

Moscow

elenlys@gmail.comМедицинский радиологический научный центр имени А.Ф. Цыба – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России; Обнинский институт атомной энергетики – филиал ФГАОУ ВО «Национальный исследовательский ядерный университет «МИФИ»РоссияMedical Radiological Research Center n.a. A. F. Tsyb – a branch of Federal Medical and Biological Centre ‘National Medical Research Centre for Radiology;Obninsk Institute for Nuclear Power Engineering – National Research Nuclear University MEPhI (Moscow Engineering Physics Institute)Russian FederationМедицинский радиологический научный центр имени А.Ф. Цыба – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава РоссииБеларусьMedical Radiological Research Center n.a. A. F. Tsyb – a branch of Federal Medical and Biological Centre ‘National Medical Research Centre for RadiologyBelarusФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии имени Дмитрия Рогачева» Минздрава РоссииРоссияNational Medical Research Centre for Pediatric Hematology, Oncology and Immunology n.a. Dmitry RogachyovRussian Federation202106122021131«Диагностика и онкотерапия» (3)1318Copyright © Абакушина Е.В., Гельм Ю.В., Лысюк Е.Ю., 20212021Абакушина Е.В., Гельм Ю.В., Лысюк Е.Ю.Abakushina E.V., Gel’m Y.V., Lyssuk E.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-alphabet.com/jour/article/view/2311

Описан способ активации лимфоцитов, выделенных из периферической крови больных меланомой, и культивируемых в среде, дополненной IL‑2 и IL‑15. Было показано, что в данной среде лимфоциты обладают повышенным пролиферативным и активационным потенциалом. Комбинация цитокинов оказывает положительное влияние на экспрессию маркеров активации NK- и Т-лимфоцитов (CD38, CD69, CD25, HLA-DR и NKG2D), цитотоксичность, жизнеспособность и может быть рекомендована для культивирования лимфоцитов больных меланомой с целью проведения адоптивной иммунотерапии.

This article describes a method for activating lymphocytes isolated from the peripheral blood of melanoma patients and cultured in a medium supplemented with IL‑2 and IL‑15. It was shown that in these terms, lymphocytes have an increased proliferative and activation potential. The combination of cytokines has a positive effect on cytotoxicity, viability and the expression of activation markers (CD38, CD69, CD25, HLA-DR and NKG2D) on NK- and T-lymphocyte, and may be recommended for the culture of lymphocytes in melanoma patients for the purpose of adoptive immunotherapy.

активация лимфоцитовIL 2IL 15естественные киллерные клеткиадоптивная иммунотерапиямеланомаactivation of lymphocytesIL 2IL 15natural killer cellsadoptive immunotherapymelanomaReferencesShin M.H., Kim J., Lim S.A., et al. NK cell-based immunotherapies in cancer. Immune Netw. 2020; 20 (2). https://doi.org/10.4110/in.2020.20.e14Shin M.H., Kim J., Lim S.A., et al. NK cell-based immunotherapies in cancer. Immune Netw. 2020; 20 (2). https://doi.org/10.4110/in.2020.20.e14Абакушина Е. В., Козлов И. Г. Иммунотерапия с использованием естественных киллеров в лечении онкологических заболеваний. Российский иммунологический журнал. 2016; 10 (19), № 2: 131–142.Abakushina E.V., Kozlov I.G. Immunotherapy with natural killer cells in the treatment of cancer. Russian Journal of Immunology. 2016; 10 (19), No. 2: 131–142.Hofer E., Koehl U. Natural killer cell-based cancer immunotherapies: from immune evasion to promising targeted cellular therapies. Frontiers in Immunology. 2017; 8. https://doi.org/10.3389/fimmu.2017.00745Hofer E., Koehl U. Natural killer cell-based cancer immunotherapies: from immune evasion to promising targeted cellular therapies. Frontiers in Immunology. 2017; 8. https://doi.org/10.3389/fimmu.2017.00745Hu W., Wang G., Huang D., et al. Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front. Immunol. 2019; 10: 1205. https://doi.org/10.3389/fimmu.2019.01205Hu W., Wang G., Huang D., et al. Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front. Immunol. 2019; 10: 1205. https://doi.org/10.3389/fimmu.2019.01205Dahlberg C. I., Sarhan D., Chrobok M., et al. Natural Killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumor activity. Frontiers in Immunology. 2015; 6: 605. https://doi.org/10.3389/ fimmu.2015.00605Dahlberg C. I., Sarhan D., Chrobok M., et al. Natural Killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumor activity. Frontiers in Immunology. 2015; 6: 605. https://doi.org/10.3389/ fimmu.2015.00605Zhang C., Hu Y., Shi C. Targeting Natural Killer cells for tumor immunotherapy. Front. Immunol. 2020; 11: 60. https://doi.org/10.3389/fimmu.2020.00060Zhang C., Hu Y., Shi C. Targeting Natural Killer cells for tumor immunotherapy. Front. Immunol. 2020; 11: 60. https://doi.org/10.3389/fimmu.2020.00060Abakushina E. V., Gelm Yu.V., Pasova I. A., Bazhin A. V. Immunotherapeutic approaches for the treatment of colorectal cancer. Biochemistry (Moscow). 2019; 84 (7): 720–728. https://doi.org/10.1134/S 0006297919070046Abakushina E. V., Gelm Yu.V., Pasova I. A., Bazhin A. V. Immunotherapeutic approaches for the treatment of colorectal cancer. Biochemistry (Moscow). 2019; 84 (7): 720–728. https://doi.org/10.1134/S 0006297919070046Gel’m Yu.V., Kuz’mina E.G., Abakushina E. V. Functional activity of lymphocytes of healthy donors and cancer patients after culturing with IL 2 and IL 15. Bulletin of Experimental Biology and Medicine. 2019; 167 (4): 486–491. https://doi.org/10.1007/s10517–019–04556–3Gel’m Yu.V., Kuz’mina E.G., Abakushina E. V. Functional activity of lymphocytes of healthy donors and cancer patients after culturing with IL 2 and IL 15. Bulletin of Experimental Biology and Medicine. 2019; 167 (4): 486–491. https://doi.org/10.1007/s10517–019–04556–3Кит О. И., Кириченко Е.Ю., Новикова И. А. и соавт. Иммунотерапия колоректального рака: современное состояние и перспективы (обзор). Современные технологии в медицине. 2017; 9 (3): 138–150.Kit О. I., Kirichenko Е.Y., Novikova I.А., Maksimov А.Y., Filippova S.Y., Grankina А.О., Zlatnik Е.Y. Colorectal Cancer Immunotherapy: Current State and Prospects (Review). Modern Technologies in Medicine. 2017; 9 (3): 138–150. https://doi.org/10.17691/stm2017.9.3.18Miller J. S., Soignier Y. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005; 105 (8): 3051–3057. https://doi.org/10.1182/blood 2004–07–2974Miller J. S., Soignier Y. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005; 105 (8): 3051–3057. https://doi.org/10.1182/blood 2004–07–2974Kmiecik J., Zimmer J., Chekenya M. Natural killer cells in intracranial neoplasms: presence and therapeutic efficacy against brain tumours. Neuro-Oncology. 2014; 116 (1): 1–9. https://doi.org/10.1007/s11060–013–1265–5Kmiecik J., Zimmer J., Chekenya M. Natural killer cells in intracranial neoplasms: presence and therapeutic efficacy against brain tumours. Neuro-Oncology. 2014; 116 (1): 1–9. https://doi.org/10.1007/s11060–013–1265–5Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Cancers (Basel). 2020; 12 (6): 1553. https://doi. org/10.3390/cancers12061553Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Cancers (Basel). 2020; 12 (6): 1553. https://doi. org/10.3390/cancers12061553Granzin M., Wagner J., Kohl U., et al. Shaping of Natural killer cell antitumor activity by ex vivo cultivation. Frontiers in Immunology. 2017; 8: 458. https://doi. org/10.3389/fimmu.2017.00458Granzin M., Wagner J., Kohl U., et al. Shaping of Natural killer cell antitumor activity by ex vivo cultivation. Frontiers in Immunology. 2017; 8: 458. https://doi. org/10.3389/fimmu.2017.00458Dafni U., Michielin O., Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant Interleukin 2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol. 2019; 30 (12): 1902–1913. https://doi.org/10.1093/annonc/mdz398Dafni U., Michielin O., Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant Interleukin 2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol. 2019; 30 (12): 1902–1913. https://doi.org/10.1093/annonc/mdz398Wang K., Han Y., Cho W.C., Zhu H. The rise of human stem cell-derived natural killer cells for cancer immunotherapy. Expert Opinion Biological Therapy. 2019; 19 (2): 141–148. https://doi.org/10.1080/14712598.2019.1559293Wang K., Han Y., Cho W.C., Zhu H. The rise of human stem cell-derived natural killer cells for cancer immunotherapy. Expert Opinion Biological Therapy. 2019; 19 (2): 141–148. https://doi.org/10.1080/14712598.2019.1559293Титов К. С., Демидов Л. В., Киселевский М. В. и соавт. Интраплевральная ИЛ 2 иммунотерапия пациентов с метастатичискими плевритами. Российский онкологический журнал. 2010; 4: 20–24.Titov K. S., Demidov L. V., Kiselevsky M. V. et al. Intrapleural IL 2 immunotherapy of patients with metastatic pleurisy. Russian Journal of Oncology. 2010; 4: 20–24.Chen Z., Chen L., Baker K. et al. CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells. Journal of Experimental Medicine. 2011; 208 (13): 2633–40. https://doi.org/10.1084/ jem.20102575Chen Z., Chen L., Baker K. et al. CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells. Journal of Experimental Medicine. 2011; 208 (13): 2633–40. https://doi.org/10.1084/ jem.20102575Sangiolo D., Martinuzzi E., Todorovic M., et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. Int Imm. 2008; 20 (7): 841–848. https://doi.org/10.1093/intimm/dxn042Sangiolo D., Martinuzzi E., Todorovic M., et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. Int Imm. 2008; 20 (7): 841–848. https://doi.org/10.1093/intimm/dxn042Wang F. S., Liu M.X., Zhang B., et al. Antitumor activities of human autologous cytokine-induced killer (CIK) cells against hepatocellular carcinoma cells in vitro and in vivo. World J Gastroenterol. 2002; 8 (3): 464–468. doi: 10.3748/ wjg.v8.i3.464.Wang F. S., Liu M.X., Zhang B., et al. Antitumor activities of human autologous cytokine-induced killer (CIK) cells against hepatocellular carcinoma cells in vitro and in vivo. World J Gastroenterol. 2002; 8 (3): 464–468. doi: 10.3748/ wjg.v8.i3.464.Oh S., Lee J.H., Kwack K., Choi S.W. Natural Killer cell therapy: a new treatment paradigm for solid tumors. Cancers (Basel). 2019; 11 (10): 1534. https://doi. org/10.3390/cancers11101534Oh S., Lee J.H., Kwack K., Choi S.W. Natural Killer cell therapy: a new treatment paradigm for solid tumors. Cancers (Basel). 2019; 11 (10): 1534. https://doi. org/10.3390/cancers11101534Abakushina E. V., Marizina Yu.V., Kaprin A.D. Morphofunctional characteristics of human lymphocytes after in vitro activation. Bulletin of Experimental Biology and Medicine. 2016; 161 (5): 731–735. https://doi.org/10.1007/ s10517–016–3496-xAbakushina E. V., Marizina Yu.V., Kaprin A.D. Morphofunctional characteristics of human lymphocytes after in vitro activation. Bulletin of Experimental Biology and Medicine. 2016; 161 (5): 731–735. https://doi.org/10.1007/ s10517–016–3496-xЧикилева И. О., Велижева Н. П., Шубина И. Ж., и соавт. Содержание Т-регуляторных лимфоцитов CD4+CD25+FOXP3+ в популяции лимфокинактивированных киллеров. Вестник РОНЦ им. Н.Н. Блохина РАМН. 2008; 19 (3): 16–25.Chikileva I. O., Velizheva N. P., Shubina I. Zh., et al. Content of t-regulatory lymphocytes CD4+CD25+FOXP3+ in lymphokine-activated killer population. Journal of N.N. Blokhin Russian Cancer Research. 2008; 19, 3: 16–25.Ахматова Н. К., Лебединская Е. А., Лебединская О. В., Киселевский М. В. Натуральные киллеры Т-клетки (НКТ), иммунофенотипическая и функциональная характеристика, активация, значение в практической медицине. Российский иммунологический журнал. 2007; 1 (10), 3–4: 195–206.Akhmatova N.K., Lebedinskaya E.A., Lebedinskaya O.V., Kiselevsky M.V. Natural Killer T (NKT) cells: immunophenotype, functional characteristics and significance in clinical practice. Russian Journal of Immunology. 2007; 1 (10), 3–4: 195–206.Mao Y., van Hoef V., Zhang X., et al. Blood. IL 15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. 2016; 128 (11). https://doi.org/10.1182/blood 2016–02–698027Mao Y., van Hoef V., Zhang X., et al. Blood. IL 15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. 2016; 128 (11). https://doi.org/10.1182/blood 2016–02–698027Lin S. J., Lee P. T., Kuo M. L. Cytokine activation of natural killer cells. Methods in molecular biology. 2014; 1139: 223–229. https://doi.org/10.1007/978–1– 4939–0345–0_19Lin S. J., Lee P. T., Kuo M. L. Cytokine activation of natural killer cells. Methods in molecular biology. 2014; 1139: 223–229. https://doi.org/10.1007/978–1– 4939–0345–0_19Юрова К. А., Хазиахматова О. Г., Дунец Н. А., Тодосенко Н. М., Шуплецова В. В., Литвинова Л. С. Влияние цитокинов (IL 2, IL 7 и IL 15), имеющих общую g-цепь рецепторов, на дифференцировку и созревание T-клеток CD4+/CD8+ в популяции Т-лимфоцитов CD45RA in vitro. Цитология. 2017; 59 (5): 337–342.Yurova K.A., Khaziakhmatova O.G., Dunets N.A., Todosenko N.M., Shupletsova V. V., Litvinova L. S. Effect of cytokines (IL 2, IL 7 and IL 15), having a common g-chain of receptors on differentiation and maturation of CD 4+/ CD8+ T-cells in a CD45RA T-lymphocytes population in vitro. Cell and Tissue Biology. 2017; 11 (5): 356–362.Conlon K. C., Lugli E., Welles H. C., Rosenberg S.A. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin 15 in patients with cancer. J Clin Oncol. 2015; 33 (1): 74–82. https://doi. org/10.1200/JCO.2014.57.3329Conlon K. C., Lugli E., Welles H. C., Rosenberg S.A. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin 15 in patients with cancer. J Clin Oncol. 2015; 33 (1): 74–82. https://doi. org/10.1200/JCO.2014.57.3329

The authors declare that there are no conflicts of interest present.