oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2023-22-1-43-54oncotomsk-2430Research ArticleЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯLABORATORY AND EXPERIMENTAL STUDIESЭкспрессия рецепторов цитокинов с общей Ɣ-цепью как маркеров функциональных фенотипов PD-1 и TIM-3-позитивных Т-клеток при множественной миеломCommon Ɣ-chain cytokine receptors as functional phenotype markers of PD-1and TIM-3-positive T cells in multiple myelomahttps://orcid.org/0000-0003-2902-9336БаторовЕ. В.BatorovE. V.

Баторов Егор Васильевич, кандидат медицинских наук, старший научный сотрудник лаборатории клеточной иммунотерапии

630099, г. Новосибирск, ул. Ядринцевская, 14

SPIN-код: 6316-0759,

Researcher ID (WOS): L-8628-2015,

Author ID (Scopus): 35768879800

Egor V. Batorov, MD, PhD, Senior Researcher, Laboratory of Cellular Immunotherapy

14, Yadrintsevskaya St., 630099, Novosibirsk

Researcher ID (WOS): L-8628-2015,

Author ID (Scopus): 35768879800

ebatorov@mail.ruhttps://orcid.org/0000-0002-4885-8327АристоваТ. А.AristovaV. A.

Аристова Татьяна Андреевна, врач-гематолог гематологического отделения с блоком трансплантации костного мозга

630099, г. Новосибирск, ул. Ядринцевская, 14

Tatyana A. Aristova, MD, Hematologist, Hematology Department with Bone Marrow Transplantation Unit

14, Yadrintsevskaya St., 630099, Novosibirsk

https://orcid.org/0000-0003-1822-6326УшаковаГ. Ю.UshakovaG. Yu.

Ушакова Галина Юрьевна, кандидат медицинских наук, врач-гематолог гематологического отделения с блоком трансплантации костного мозга

630099, г. Новосибирск, ул. Ядринцевская, 14

Galina Yu. Ushakova, MD, PhD, Hematologist, Hematology Department with Bone Marrow Transplantation Unit

14, Yadrintsevskaya St., 630099, Novosibirsk

https://orcid.org/0000-0001-7109-3839СизиковаС. А.SizikovaS. A.

Сизикова Светлана Анатольевна, кандидат медицинских наук, врач-гематолог гематологического отделения с блоком трансплантации костного мозга

630099, г. Новосибирск, ул. Ядринцевская, 14

Svetlana A. Sizikova, MD, PhD, Hematologist, Hematology Department with Bone Marrow Transplantation Unit

14, Yadrintsevskaya St., 630099, Novosibirsk

https://orcid.org/0000-0003-1951-2260ДенисоваВ. В.DenisovaV. V.

Денисова Вера Васильевна, кандидат медицинских наук, заведующая гематологическим отделением с блоком трансплантации костного мозга

630099, г. Новосибирск, ул. Ядринцевская, 14

SPIN-код: 5507-1870,

Author ID (Scopus): 54881246800

Vera V. Denisova, MD, PhD, Head of the Hematology Department with a Bone Marrow Transplantation Unit

14, Yadrintsevskaya St., 630099, Novosibirsk

Author ID (Scopus): 54881246800

https://orcid.org/0000-0001-8997-3586ШевелаЕ. Я.ShevelaE. Ya.

Шевела Екатерина Яковлевна, доктор медицинских наук, ведущий научный сотрудник лаборатории клеточной иммунотерапии

630099, г. Новосибирск, ул. Ядринцевская, 14

Researcher ID (WOS): Y-6730-2018,

Author ID (Scopus): 14013896300

Ekaterina Ya. Shevela, MD, DSc, Leading Researcher, Laboratory of Cellular Immunotherapy, Research Institute of Fundamental and Clinical Immunology (Novosibirsk, Russia)

14, Yadrintsevskaya St., 630099, Novosibirsk

Researcher ID (WOS): Y-6730-2018,

Author ID (Scopus): 14013896300

https://orcid.org/0000-0001-6895-938XОстанинА. А.OstaninA. A.

Останин Александр Анатольевич, доктор медицинских наук, профессор, главный научный сотрудник лаборатории клеточной иммунотерапии

630099, г. Новосибирск, ул. Ядринцевская, 14

SPIN-код: 3199-0970,

Researcher ID (WOS): Y-6591-2018,

Author ID (Scopus): 6701440111

Alexander A. Ostanin, MD, Professor, Chief Researcher of the Laboratory of Cellular Immunotherapy

14, Yadrintsevskaya St., 630099, Novosibirsk

Researcher ID (WOS): Y-6591-2018,

Author ID (Scopus): 6701440111

ЧерныхЕ. Р.ChernykhE. R.

Черных Елена Рэмовна, доктор медицинских наук, профессор, член-корреспондент РАН, заведующая лабораторией клеточной иммунотерапии

630099, г. Новосибирск, ул. Ядринцевская, 14

SPIN-код: 8957-0362,

Researcher ID (WOS): K-1052-2014,

Author ID (Scopus): 7003649977

Elena R. Chernykh, MD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Cellular Immunotherapy

14, Yadrintsevskaya St., 630099, Novosibirsk

Researcher ID (WOS): K-1052-2014,

Author ID (Scopus): 7003649977

ФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии»РоссияResearch Institute of Fundamental and Clinical ImmunologyRussian Federation2023220220232214354Copyright © Баторов Е.В., Аристова Т.А., Ушакова Г.Ю., Сизикова С.А., Денисова В.В., Шевела Е.Я., Останин А.А., Черных Е.Р., 20232023Баторов Е.В., Аристова Т.А., Ушакова Г.Ю., Сизикова С.А., Денисова В.В., Шевела Е.Я., Останин А.А., Черных Е.Р.Batorov E.V., Aristova V.A., Ushakova G.Y., Sizikova S.A., Denisova V.V., Shevela E.Y., Ostanin A.A., Chernykh E.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2430

Т-клетки, экспрессирующие чек-поинт рецепторы PD-1, TIM-3 и др., являются потенциальной мишенью для таргетной иммунотерапии при множественной миеломе (ММ), однако включают в себя различные популяции клеток, дисрегуляция которых может приводить к развитию нежелательных реакций.

Целью исследования явилось изучение маркеров активации, рецепторов гомеостатических цитокинов и транскрипционных факторов, экспрессируемых PD-1и TIM-3-позитивными Т-клетками у больных ММ на этапе индукционной терапии.

Материал и методы

Материал и методы. Было исследовано относительное содержание циркулирующих PD-1и/или TIM-3-позитивных и негативных Т-клеток, экспрессирующих рецепторы цитокинов с общей γ-цепью CD25, CD122, CD127, фосфорилированный STAT5 и транскрипционный фактор EOMES, ассоциированный с Т-клеточным истощением, методом проточной цитометрии у 17 здоровых доноров, 22 больных ММ в состоянии ремиссии и 7 больных ММ с прогрессирующим течением.

Результаты

Результаты. Пул T-лимфоцитов, экспрессирующих ингибиторные чек-поинт рецепторы PD-1 и/или TIM-3, у больных ММ включал в себя: CD25+EOMESактивированные клетки, CD4+CD25+CD127-FOXP3+ регуляторные Т-клетки (Трег), CD4+CD25-EOMES+ дисфункциональные клетки. CD25+ Т-клетки здоровых доноров и больных ММ независимо от экспрессии исследованных чек-поинт рецепторов были EOMESнегативными. Не выявлено такой ассоциации для рецепторов цитокинов CD122 и CD127. EOMES в большей степени является маркером Т-клеточного истощения для CD4+ Т-клеток, но не для CD8+ Т-клеток, в которых он более ассоциирован с активацией. Доля CD4+ Трег среди циркулирующих PD-1+ и TIM-3+ Т-клеток была относительно невысока. Более высокое содержание рецепторов цитокинов в популяции TIM-3+ Т-клеток может свидетельствовать о преимущественном вовлечении TIM-3 в контроль гомеостатической пролиферации зрелых Т-клеток в условиях лимфопении, в то время как экспрессия PD-1 может быть более ассоциирована с регуляцией активации через Т-клеточной рецептор. Уровни PD-1+ и/или TIM-3+ активированных, дисфункциональных и регуляторных Т-клеток в перспективе могут быть использованы для прогноза безопасности и эффективности таргетной иммунотерапии.

T cells expressing checkpoint receptors PD-1, TIM-3 etc., are potential targets for monoclonal antibody immunotherapy in multiple myeloma (MM). However, checkpoint expressing T cell compartment includes different subsets, and their dysregulation following anti-checkpoint therapy can lead to the development of adverse events.

The aim of this study was to evaluate activation markers – homeostatic cytokine receptors and transcription factors expressed by PD-1and TIM-3-positive T cells.

Material and Methods

Material and Methods. Relative counts of circulating PD-1and/or TIM-3-positive and negative T cells expressing common ɣ-chain cytokine receptors CD25, CD122, CD127, phosphorylated STAT5, and transcription factor EOMES associated with T cell exhaustion were studied using flow cytometry in 17 healthy donors, 22 MM patients with remission and 7 MM patients with progressive disease.

Results

Results. T cells expressing PD-1 and/or TIM-3 inhibitory checkpoint receptors in MM patients consisted of CD25+EOMESactivated cells, CD4+CD25+CD127-FOXP3+ regulatory T cells (Treg), CD4+CD25-EOMES+ dysfunctional cells. CD25+ T cells from healthy donors and MM patients, regardless of the expression of the studied checkpoint receptors, were EOMES-negative. No such association was found for CD122 and CD127 cytokine receptors. EOMES is a marker of T cell exhaustion for CD4+ T cells, but not for CD8+ T cells, in which it is more associated with activation. The proportion of CD4+ Tregs among circulating PD-1+ and TIM-3+ T cells was relatively low. A higher content of cytokine receptors in the population of TIM-3+ T cells may indicate the predominant involvement of TIM-3 in the control of homeostatic proliferation of mature T cells under lymphopenic conditions, while the expression of PD-1 may be more associated with the regulation of activation through T cell receptor. PD-1+ and/or TIM-3+ levels of activated, dysfunctional, and regulatory T cells can potentially be used to predict the safety and efficacy of targeted immunotherapy.

множественная миеломаPD-1TIM-3CD25CD122EOMESТ-клеточное истощениерегуляторные Т-клеткиmultiple muelomaPD-1TIM-3CD25CD122EOMEST cell exhaustionregulatory T cellsРезультаты исследования экспрессии Т-клетками рецепторов PD-1, TIM-3, CD25, CD122, CD127 и внутриклеточной экспрессии pSTAT5 получены за счет средств Российского научного фонда (проект № 20-75-10132). Результаты исследования внутриклеточной экспрессии EOMES и регуляторных Т-клеток выполнены в рамках государственного задания 2021-2023 № 122011800353-4The results of the study concerning T cell expression of PD-1, TIM-3, CD25, CD122, CD127 and intracellular expression of pSTAT5 were obtained within the Russian Science Foundation grant (project № 20-75-10132). The results of the study concerning EOMES intracellular expression and regulatory T cell counts were carried out within the framework No 122011800353-4ReferencesKazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016; 43(6): 676–81. doi: 10.1053/j.seminoncol.2016.11.004.Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016; 43(6): 676–81. doi: 10.1053/j.seminoncol.2016.11.004.Cowan A.J., Green D.J., Kwok M., Lee S., Coffey D.G., Holmberg L.A., Tuazon S., Gopal A.K., Libby E.N. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022; 327(5): 464–77. doi: 10.1001/jama.2022.0003.Cowan A.J., Green D.J., Kwok M., Lee S., Coffey D.G., Holmberg L.A., Tuazon S., Gopal A.K., Libby E.N. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022; 327(5): 464–77. doi: 10.1001/jama.2022.0003.Zelle-Rieser C., Thangavadivel S., Biedermann R., Brunner A., Stoitzner P., Willenbacher E., Greil R., Jöhrer K. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J Hematol Oncol. 2016; 9(1): 116. doi: 10.1186/s13045-016-0345-3.Zelle-Rieser C., Thangavadivel S., Biedermann R., Brunner A., Stoitzner P., Willenbacher E., Greil R., Jöhrer K. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J Hematol Oncol. 2016; 9(1): 116. doi: 10.1186/s13045-016-0345-3.Tan J., Chen S., Huang J., Chen Y., Yang L., Wang C., Zhong J., Lu Y., Wang L., Zhu K., Li Y. Increased exhausted CD8+ T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma. Asia Pac J Clin Oncol. 2018; 14(5): 266–74. doi: 10.1111/ajco.13033.Tan J., Chen S., Huang J., Chen Y., Yang L., Wang C., Zhong J., Lu Y., Wang L., Zhu K., Li Y. Increased exhausted CD8+ T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma. Asia Pac J Clin Oncol. 2018; 14(5): 266–74. doi: 10.1111/ajco.13033.Görgün G., Samur M.K., Cowens K.B., Paula S., Bianchi G., Anderson J.E., White R.E., Singh A., Ohguchi H., Suzuki R., Kikuchi S., Harada T., Hideshima T., Tai Y.T., Laubach J.P., Raje N., Magrangeas F., Minvielle S., Avet-Loiseau H., Munshi N.C., Dorfman D.M., Richardson P.G., Anderson K.C. Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma. Clin Cancer Res. 2015; 21(20): 4607–18. doi: 10.1158/1078-0432.CCR-15-0200.Görgün G., Samur M.K., Cowens K.B., Paula S., Bianchi G., Anderson J.E., White R.E., Singh A., Ohguchi H., Suzuki R., Kikuchi S., Harada T., Hideshima T., Tai Y.T., Laubach J.P., Raje N., Magrangeas F., Minvielle S., Avet-Loiseau H., Munshi N.C., Dorfman D.M., Richardson P.G., Anderson K.C. Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma. Clin Cancer Res. 2015; 21(20): 4607–18. doi: 10.1158/1078-0432.CCR-15-0200.Batorov E.V., Aristova T.A., Sergeevicheva V.V., Sizikova S.A., Ushakova G.Y., Pronkina N.V., Shishkova I.V., Shevela E.Y., Ostanin A.A., Chernykh E.R. Quantitative and functional characteristics of circulating and bone marrow PD-1and TIM-3-positive T cells in treated multiple myeloma patients. Sci Rep. 2020; 10(1). doi:10.1038/s41598-020-77941-y.Batorov E.V., Aristova T.A., Sergeevicheva V.V., Sizikova S.A., Ushakova G.Y., Pronkina N.V., Shishkova I.V., Shevela E.Y., Ostanin A.A., Chernykh E.R. Quantitative and functional characteristics of circulating and bone marrow PD-1and TIM-3-positive T cells in treated multiple myeloma patients. Sci Rep. 2020; 10(1). doi:10.1038/s41598-020-77941-y.Wherry E.J., Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15(8): 486–99. doi: 10.1038/nri3862.Wherry E.J., Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15(8): 486–99. doi: 10.1038/nri3862.Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020; 11(1): 3801. doi: 10.1038/s41467-02017670-y.Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020; 11(1): 3801. doi: 10.1038/s41467-02017670-y.Usmani S.Z., Schjesvold F., Oriol A., Karlin L., Cavo M., Rifkin R.M., Yimer H.A., LeBlanc R., Takezako N., McCroskey R.D., Lim A.B.M., Suzuki K., Kosugi H., Grigoriadis G., Avivi I., Facon T., Jagannath S., Lonial S., Ghori R.U., Farooqui M.Z.H., Marinello P., SanMiguel J.; KEYNOTE-185 Investigators. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019; 6(9): 448–58. doi: 10.1016/S2352-3026(19)30109-7.Usmani S.Z., Schjesvold F., Oriol A., Karlin L., Cavo M., Rifkin R.M., Yimer H.A., LeBlanc R., Takezako N., McCroskey R.D., Lim A.B.M., Suzuki K., Kosugi H., Grigoriadis G., Avivi I., Facon T., Jagannath S., Lonial S., Ghori R.U., Farooqui M.Z.H., Marinello P., SanMiguel J.; KEYNOTE-185 Investigators. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019; 6(9): 448–58. doi: 10.1016/S2352-3026(19)30109-7.Mateos M.V., Blacklock H., Schjesvold F., Oriol A., Simpson D., George A., Goldschmidt H., Larocca A., Chanan-Khan A., Sherbenou D., Avivi I., Benyamini N., Iida S., Matsumoto M., Suzuki K., Ribrag V., Usmani S.Z., Jagannath S., Ocio E.M., Rodriguez-Otero P., San Miguel J., Kher U., Farooqui M., Liao J., Marinello P., Lonial S.; KEYNOTE-183 Investigators. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019; 6(9): 459–69. doi: 10.1016/S2352-3026(19)30110-3.Mateos M.V., Blacklock H., Schjesvold F., Oriol A., Simpson D., George A., Goldschmidt H., Larocca A., Chanan-Khan A., Sherbenou D., Avivi I., Benyamini N., Iida S., Matsumoto M., Suzuki K., Ribrag V., Usmani S.Z., Jagannath S., Ocio E.M., Rodriguez-Otero P., San Miguel J., Kher U., Farooqui M., Liao J., Marinello P., Lonial S.; KEYNOTE-183 Investigators. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019; 6(9): 459–69. doi: 10.1016/S2352-3026(19)30110-3.Kinter A.L., Godbout E.J., McNally J.P., Sereti I., Roby G.A., O'Shea M.A., Fauci A.S. 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.181.10.6738.Kinter A.L., Godbout E.J., McNally J.P., Sereti I., Roby G.A., O'Shea M.A., Fauci A.S. 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.181.10.6738.Mujib S., Jones R.B., Lo C., Aidarus N., Clayton K., Sakhdari A., Benko E., Kovacs C., Ostrowski M.A. Antigen-independent induction of Tim-3 expression on human T cells by the common γ-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.1102609.Mujib S., Jones R.B., Lo C., Aidarus N., Clayton K., Sakhdari A., Benko E., Kovacs C., Ostrowski M.A. Antigen-independent induction of Tim-3 expression on human T cells by the common γ-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.1102609.Marshall N., Hutchinson K., Marron T.U., Aleynick M., Hammerich L., Upadhyay R., Svensson-Arvelund J., Brown B.D., Merad M., Brody J.D. 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-19-0391.Marshall N., Hutchinson K., Marron T.U., Aleynick M., Hammerich L., Upadhyay R., Svensson-Arvelund J., Brown B.D., Merad M., Brody J.D. 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-19-0391.Waickman A.T., Park J.Y., Park J.H. The common γ-chain cytokine receptor: tricks-and-treats for T cells. Cell Mol Life Sci. 2016; 73(2): 253–69. doi: 10.1007/s00018-015-2062-4.Waickman A.T., Park J.Y., Park J.H. The common γ-chain cytokine receptor: tricks-and-treats for T cells. Cell Mol Life Sci. 2016; 73(2): 253–69. doi: 10.1007/s00018-015-2062-4.Crawford A., Angelosanto J.M., Kao C., Doering T.A., Odorizzi P.M., Barnett B.E., Wherry E.J. Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection. Immunity. 2014; 40(2): 289–302. doi: 10.1016/j.immuni.2014.01.005.Crawford A., Angelosanto J.M., Kao C., Doering T.A., Odorizzi P.M., Barnett B.E., Wherry E.J. Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection. Immunity. 2014; 40(2): 289–302. doi: 10.1016/j.immuni.2014.01.005.Li J., He Y., Hao J., Ni L., Dong C. High Levels of Eomes Promote Exhaustion of Anti-tumor CD8+ T Cells. Front Immunol. 2018; 9: 2981. doi: 10.3389/fimmu.2018.02981.Li J., He Y., Hao J., Ni L., Dong C. High Levels of Eomes Promote Exhaustion of Anti-tumor CD8+ T Cells. Front Immunol. 2018; 9: 2981. doi: 10.3389/fimmu.2018.02981.Llaó-Cid L., Roessner P.M., Chapaprieta V., Öztürk S., Roider T., Bordas M., Izcue A., Colomer D., Dietrich S., Stilgenbauer S., Hanna B., Martín-Subero J.I., Seiffert M. EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia. Leukemia. 2021; 35(11): 3152–62. doi: 10.1038/s41375-021-01198-1.Llaó-Cid L., Roessner P.M., Chapaprieta V., Öztürk S., Roider T., Bordas M., Izcue A., Colomer D., Dietrich S., Stilgenbauer S., Hanna B., Martín-Subero J.I., Seiffert M. EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia. Leukemia. 2021; 35(11): 3152–62. doi: 10.1038/s41375-021-01198-1.Ramos-Casals M., Brahmer J.R., Callahan M.K., Flores-Chávez A., Keegan N., Khamashta M.A., Lambotte O., Mariette X., Prat A., SuárezAlmazor M.E. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020; 6(1): 38. doi: 10.1038/s41572-020-0160-6.Ramos-Casals M., Brahmer J.R., Callahan M.K., Flores-Chávez A., Keegan N., Khamashta M.A., Lambotte O., Mariette X., Prat A., SuárezAlmazor M.E. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020; 6(1): 38. doi: 10.1038/s41572-020-0160-6.Anthony S., Schluns K.S. Emerging roles for IL-15 in the activation and function of T-cells during immune stimulation. Research and Reports in Biology. 2015; 6: 25–37. doi: 10.2147/RRB.S57685.Anthony S., Schluns K.S. Emerging roles for IL-15 in the activation and function of T-cells during immune stimulation. Research and Reports in Biology. 2015; 6: 25–37. doi: 10.2147/RRB.S57685.Zhao Y., Cai C., Samir J., Palgen J.L., Keoshkerian E., Li H., Bull R.A., Luciani F., An H., Lloyd A.R. Human CD8 T-stem cell memory subsets phenotypic and functional characterization are defined by expression of CD122 or CXCR3. Eur J Immunol. 2021; 51(7): 1732–47. doi: 10.1002/eji.202049057.Zhao Y., Cai C., Samir J., Palgen J.L., Keoshkerian E., Li H., Bull R.A., Luciani F., An H., Lloyd A.R. Human CD8 T-stem cell memory subsets phenotypic and functional characterization are defined by expression of CD122 or CXCR3. Eur J Immunol. 2021; 51(7): 1732–47. doi: 10.1002/eji.202049057.Li S., Xie Q., Zeng Y., Zou C., Liu X., Wu S., Deng H., Xu Y., Li X.C., Dai Z. A naturally occurring CD8(+)CD122(+) T-cell subset as a memory-like Treg family. Cell Mol Immunol. 2014; 11(4): 326–31. doi: 10.1038/cmi.2014.25.Li S., Xie Q., Zeng Y., Zou C., Liu X., Wu S., Deng H., Xu Y., Li X.C., Dai Z. A naturally occurring CD8(+)CD122(+) T-cell subset as a memory-like Treg family. Cell Mol Immunol. 2014; 11(4): 326–31. doi: 10.1038/cmi.2014.25.Villarreal D.O., Allegrezza M.J., Smith M.A., Chin D., Luistro L.L., Snyder L.A. Targeting of CD122 enhances antitumor immunity by altering the tumor immune environment. Oncotarget. 2017; 8(65): 109151–60. doi: 10.18632/oncotarget.22642.Villarreal D.O., Allegrezza M.J., Smith M.A., Chin D., Luistro L.L., Snyder L.A. Targeting of CD122 enhances antitumor immunity by altering the tumor immune environment. Oncotarget. 2017; 8(65): 109151–60. doi: 10.18632/oncotarget.22642.Elizondo D.M., Andargie T.E., Haddock N.L., da Silva R.L.L., de Moura T.R., Lipscomb M.W. IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells are expanded by dendritic cells silenced for Allograft Inflammatory Factor-1. J Leukoc Biol. 2019; 105(1): 123–30. doi: 10.1002/JLB.1A0118-010RR.Elizondo D.M., Andargie T.E., Haddock N.L., da Silva R.L.L., de Moura T.R., Lipscomb M.W. IL-10 producing CD8+ CD122+ PD-1+ regulatory T cells are expanded by dendritic cells silenced for Allograft Inflammatory Factor-1. J Leukoc Biol. 2019; 105(1): 123–30. doi: 10.1002/JLB.1A0118-010RR.Liu H., Qiu F., Wang Y., Zeng Q., Liu C., Chen Y., Liang C.L., Zhang Q., Han L., Dai Z. CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival. Front Immunol. 2019; 10: 306. doi: 10.3389/fimmu.2019.00306.Liu H., Qiu F., Wang Y., Zeng Q., Liu C., Chen Y., Liang C.L., Zhang Q., Han L., Dai Z. CD8+CD122+PD-1+ Tregs Synergize With Costimulatory Blockade of CD40/CD154, but Not B7/CD28, to Prolong Murine Allograft Survival. Front Immunol. 2019; 10: 306. doi: 10.3389/fimmu.2019.00306.Sakuishi K., Ngiow S.F., Sullivan J.M., Teng M.W., Kuchroo V.K., Smyth M.J., Anderson A.C. TIM3+FOXP3+ regulatory T cells are tissuespecific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2013; 2(4). doi: 10.4161/onci.23849.Sakuishi K., Ngiow S.F., Sullivan J.M., Teng M.W., Kuchroo V.K., Smyth M.J., Anderson A.C. TIM3+FOXP3+ regulatory T cells are tissuespecific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2013; 2(4). doi: 10.4161/onci.23849.Banerjee H., Nieves-Rosado H., Kulkarni A., Murter B., McGrath K.V., Chandran U.R., Chang A., Szymczak-Workman A.L., Vujanovic L., Delgoffe G.M., Ferris R.L., Kane L.P. Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment. Cell Rep. 2021; 36(11). doi: 10.1016/j.celrep.2021.109699.Banerjee H., Nieves-Rosado H., Kulkarni A., Murter B., McGrath K.V., Chandran U.R., Chang A., Szymczak-Workman A.L., Vujanovic L., Delgoffe G.M., Ferris R.L., Kane L.P. Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment. Cell Rep. 2021; 36(11). doi: 10.1016/j.celrep.2021.109699.Dahlhoff J., Manz H., Steinfatt T., Delgado-Tascon J., Seebacher E., Schneider T., Wilnit A., Mokhtari Z., Tabares P., Böckle D., Rasche L., Martin Kortüm K., Lutz M.B., Einsele H., Brandl A., Beilhack A. Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression. Leukemia. 2022; 36(3): 790–800. doi: 10.1038/s41375-021-01422-y.Dahlhoff J., Manz H., Steinfatt T., Delgado-Tascon J., Seebacher E., Schneider T., Wilnit A., Mokhtari Z., Tabares P., Böckle D., Rasche L., Martin Kortüm K., Lutz M.B., Einsele H., Brandl A., Beilhack A. Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression. Leukemia. 2022; 36(3): 790–800. doi: 10.1038/s41375-021-01422-y.Kim M.J., Ha S.J. Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy. Front Cell Dev Biol. 2021; 9. doi: 10.3389/fcell.2021.767466.Kim M.J., Ha S.J. Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy. Front Cell Dev Biol. 2021; 9. doi: 10.3389/fcell.2021.767466.Pearce E.L., MullenA.C., Martins G.A., Krawczyk C.M., HutchinsA.S., Zediak V.P., Banica M., DiCioccio C.B., Gross D.A., Mao C.A., Shen H., Cereb N., Yang S.Y., Lindsten T., Rossant J., Hunter C.A., Reiner S.L. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003; 302(5647): 1041–3. doi: 10.1126/science.1090148.Pearce E.L., MullenA.C., Martins G.A., Krawczyk C.M., HutchinsA.S., Zediak V.P., Banica M., DiCioccio C.B., Gross D.A., Mao C.A., Shen H., Cereb N., Yang S.Y., Lindsten T., Rossant J., Hunter C.A., Reiner S.L. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003; 302(5647): 1041–3. doi: 10.1126/science.1090148.Intlekofer A.M., Takemoto N., Wherry E.J., Longworth S.A., Northrup J.T., Palanivel V.R., Mullen A.C., Gasink C.R., Kaech S.M., Miller J.D., Gapin L., Ryan K., Russ A.P., Lindsten T., Orange J.S., Goldrath A.W., Ahmed R., Reiner S.L. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005; 6(12): 1236–44. doi: 10.1038/ni1268. Erratum in: Nat Immunol. 2006; 7(1): 113.Intlekofer A.M., Takemoto N., Wherry E.J., Longworth S.A., Northrup J.T., Palanivel V.R., Mullen A.C., Gasink C.R., Kaech S.M., Miller J.D., Gapin L., Ryan K., Russ A.P., Lindsten T., Orange J.S., Goldrath A.W., Ahmed R., Reiner S.L. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005; 6(12): 1236–44. doi: 10.1038/ni1268. Erratum in: Nat Immunol. 2006; 7(1): 113.Paley M.A., Kroy D.C., Odorizzi P.M., Johnnidis J.B., Dolfi D.V., Barnett B.E., Bikoff E.K., Robertson E.J., Lauer G.M., Reiner S.L., Wherry E.J. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012; 338(6111): 1220–5. doi: 10.1126/science.1229620.Paley M.A., Kroy D.C., Odorizzi P.M., Johnnidis J.B., Dolfi D.V., Barnett B.E., Bikoff E.K., Robertson E.J., Lauer G.M., Reiner S.L., Wherry E.J. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012; 338(6111): 1220–5. doi: 10.1126/science.1229620.

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