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Мембранные (CD8⁺PD-1⁺ и CD4⁺PD-1⁺) и растворимые (sPD-1 и sPD-L1) формы контрольных точек иммунитета у больных меланомой, раком молочной железы и раком слизистой оболочки полости рта
Мембранные (CD8⁺PD-1⁺ и CD4⁺PD-1⁺) и растворимые (sPD-1 и sPD-L1) формы контрольных точек иммунитета у больных меланомой, раком молочной железы и раком слизистой оболочки полости рта
Заботина Т.Н., Черткова А.И., Борунова А.А., Кушлинский Н.Е., Герштейн Е.С., Захарова Е.Н., Шоуа Э.К., Циклаури В.Т., Самойленко И.В., Хорошилов М.В., Кадагидзе З.Г. Мембранные (CD8⁺PD-1⁺ и CD4+PD-1⁺) и растворимые (sPD-1 и sPD-L1) формы контрольных точек иммунитета у больных меланомой, раком молочной железы и раком слизистой оболочки полости рта. Современная Онкология. 2023;25(3):301–307. DOI: 10.26442/18151434.2023.3.202443
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
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Аннотация
Обоснование. PD-1-/PD-L1-путь занимает важное место в ускользании опухоли от иммунологического надзора. Помимо мембранных форм PD-1 и PD-L1 существуют растворимые варианты (soluble) – sPD-1 и sPD-L1. Как мембранные, так и растворимые формы обладают иммунорегуляторными свойствами и могут воздействовать на функцию и количество различных популяций иммунных клеток.
Цель. Изучить взаимосвязь процентного содержания мембранных (CD8⁺PD-1⁺ и CD4+PD-1⁺ лимфоцитов) и растворимых форм (sPD-1 и sPD-L1) с уровнем основных эффекторных и регуляторных популяций лимфоцитов периферической крови (ПК) и лимфоцитов, инфильтрирующих опухоль (TILs), до лечения.
Материалы и методы. В исследование включены пациенты с меланомой, раком молочной железы и раком слизистой оболочки полости рта. Методом проточной цитофлуориметрии определяли процентное содержание клеток основных популяций лимфоцитов ПК и TILs. Концентрации белков sPD-1 и sPD-L1 исследовали в сыворотке крови с помощью иммуноферментного анализа.
Результаты. В ПК и опухолевой ткани уровень CD8⁺PD-1⁺ клеток был взаимосвязан с определенными популяциями CD8 лимфоцитов, в ПК у больных меланомой – с популяциями CD8⁺CD11b⁺CD28⁺ и регуляторных CD8⁺CD11b⁻CD28⁻ Т-клеток, у больных раком молочной железы – с популяцией CD8⁺CD11b⁺CD28⁺ лимфоцитов, в опухолевой ткани у всех исследованных больных – с популяцией регуляторных CD8⁺CD11b⁻CD28⁻ Т-клеток. Подтверждены иммунорегуляторные свойства растворимых форм sPD-1 и sPD-L1: показана положительная взаимосвязь уровня данных маркеров с процентным содержанием супрессорных CD8⁺CD11b⁻CD28⁻ Т-клеток и отрицательная – с процентным содержанием CD8 лимфоцитов и CD8⁺CD11b⁺CD28⁺ цитотоксических/памяти Т-клеток, В-клеток и активированных CD25 лимфоцитов.
Заключение. Результаты проведенного исследования могут внести определенный вклад в изучение прогностической значимости мембранных и растворимых форм PD-1 и PD-L1 с учетом особенностей их взаимосвязи с супрессорными и эффекторными популяциями лимфоцитов системного и локального иммунитета.
Ключевые слова: меланома, рак молочной железы, рак слизистой оболочки полости рта, лимфоциты периферической крови, инфильтрирующие опухоль лимфоциты, CD8⁺PD-1⁺, CD4+PD-1⁺, sPD-1, sPD-L1
Aim. To study the relationship between the initial level of CD8⁺PD-1⁺ and CD4+PD-1⁺ lymphocytes and soluble forms of sPD-1 and sPD-L1 with the percentage of the main effector and regulatory populations of peripheral blood (PB) lymphocytes and tumor-infiltrating lymphocytes.
Materials and methods. The study included melanoma, breast cancer and the oral mucosa cancer patients. The percentage of cell populations of PB lymphocytes and tumor-infiltrating lymphocytes was determined by flow cytometry before treatment. The concentrations of sPD-1 and sPD-L1 proteins were studied in blood serum using enzyme immunoassay.
Results. The relationship of the level of CD8⁺PD-1⁺ cells with certain populations of CD8-lymphocytes in PB and tumor tissue was found. In the PB of melanoma patients with CD8⁺CD11b⁺CD28⁺ and CD8⁺CD11b⁻CD28⁻ T cells, in breast cancer patients with a population of CD8⁺CD11b⁺CD28⁺ lymphocytes. In the tumor tissue of all patients there was a positive correlation with a population of regulatory CD8⁺CD11b⁻CD28⁻ T cells. The immunoregulatory properties of sPD-1 and sPD-L1 were confirmed. Both sPD-1 and sPD-L1 levels were positively correlated with the number of suppressor CD8⁺CD11b⁻CD28⁻ T cells and negatively with the level of CD8 lymphocytes, CD8⁺CD11b⁺CD28⁺ cytotoxic/memory T cells, B cells and activated CD25 lymphocytes.
Conclusion. The results of the study can make a certain contribution to the study of the prognostic significance of membrane and soluble forms of PD-1 and PD-L1, taking into account the peculiarities of their relationship with suppressor and effector populations of lymphocytes of systemic and local immunity.
Keywords: melanoma, breast cancer, cancer of the oral mucosa, peripheral blood lymphocytes, tumor-infiltrating lymphocytes, CD8⁺PD-1⁺, CD4+PD-1⁺, sPD-1, sPD-L1
Цель. Изучить взаимосвязь процентного содержания мембранных (CD8⁺PD-1⁺ и CD4+PD-1⁺ лимфоцитов) и растворимых форм (sPD-1 и sPD-L1) с уровнем основных эффекторных и регуляторных популяций лимфоцитов периферической крови (ПК) и лимфоцитов, инфильтрирующих опухоль (TILs), до лечения.
Материалы и методы. В исследование включены пациенты с меланомой, раком молочной железы и раком слизистой оболочки полости рта. Методом проточной цитофлуориметрии определяли процентное содержание клеток основных популяций лимфоцитов ПК и TILs. Концентрации белков sPD-1 и sPD-L1 исследовали в сыворотке крови с помощью иммуноферментного анализа.
Результаты. В ПК и опухолевой ткани уровень CD8⁺PD-1⁺ клеток был взаимосвязан с определенными популяциями CD8 лимфоцитов, в ПК у больных меланомой – с популяциями CD8⁺CD11b⁺CD28⁺ и регуляторных CD8⁺CD11b⁻CD28⁻ Т-клеток, у больных раком молочной железы – с популяцией CD8⁺CD11b⁺CD28⁺ лимфоцитов, в опухолевой ткани у всех исследованных больных – с популяцией регуляторных CD8⁺CD11b⁻CD28⁻ Т-клеток. Подтверждены иммунорегуляторные свойства растворимых форм sPD-1 и sPD-L1: показана положительная взаимосвязь уровня данных маркеров с процентным содержанием супрессорных CD8⁺CD11b⁻CD28⁻ Т-клеток и отрицательная – с процентным содержанием CD8 лимфоцитов и CD8⁺CD11b⁺CD28⁺ цитотоксических/памяти Т-клеток, В-клеток и активированных CD25 лимфоцитов.
Заключение. Результаты проведенного исследования могут внести определенный вклад в изучение прогностической значимости мембранных и растворимых форм PD-1 и PD-L1 с учетом особенностей их взаимосвязи с супрессорными и эффекторными популяциями лимфоцитов системного и локального иммунитета.
Ключевые слова: меланома, рак молочной железы, рак слизистой оболочки полости рта, лимфоциты периферической крови, инфильтрирующие опухоль лимфоциты, CD8⁺PD-1⁺, CD4+PD-1⁺, sPD-1, sPD-L1
________________________________________________
Aim. To study the relationship between the initial level of CD8⁺PD-1⁺ and CD4+PD-1⁺ lymphocytes and soluble forms of sPD-1 and sPD-L1 with the percentage of the main effector and regulatory populations of peripheral blood (PB) lymphocytes and tumor-infiltrating lymphocytes.
Materials and methods. The study included melanoma, breast cancer and the oral mucosa cancer patients. The percentage of cell populations of PB lymphocytes and tumor-infiltrating lymphocytes was determined by flow cytometry before treatment. The concentrations of sPD-1 and sPD-L1 proteins were studied in blood serum using enzyme immunoassay.
Results. The relationship of the level of CD8⁺PD-1⁺ cells with certain populations of CD8-lymphocytes in PB and tumor tissue was found. In the PB of melanoma patients with CD8⁺CD11b⁺CD28⁺ and CD8⁺CD11b⁻CD28⁻ T cells, in breast cancer patients with a population of CD8⁺CD11b⁺CD28⁺ lymphocytes. In the tumor tissue of all patients there was a positive correlation with a population of regulatory CD8⁺CD11b⁻CD28⁻ T cells. The immunoregulatory properties of sPD-1 and sPD-L1 were confirmed. Both sPD-1 and sPD-L1 levels were positively correlated with the number of suppressor CD8⁺CD11b⁻CD28⁻ T cells and negatively with the level of CD8 lymphocytes, CD8⁺CD11b⁺CD28⁺ cytotoxic/memory T cells, B cells and activated CD25 lymphocytes.
Conclusion. The results of the study can make a certain contribution to the study of the prognostic significance of membrane and soluble forms of PD-1 and PD-L1, taking into account the peculiarities of their relationship with suppressor and effector populations of lymphocytes of systemic and local immunity.
Keywords: melanoma, breast cancer, cancer of the oral mucosa, peripheral blood lymphocytes, tumor-infiltrating lymphocytes, CD8⁺PD-1⁺, CD4+PD-1⁺, sPD-1, sPD-L1
Полный текст
Список литературы
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2. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol. 2020;1248:33-59. DOI:10.1007/978-981-15-3266-53
3. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111-22. DOI:10.1080/21645515.2019.1571892
4. Li HY, McSharry M, Bullock B, et al. The tumor microenvironment regulates sensitivity of murine lung tumors to PD-1/PD-L1 antibody blockade. Cancer Immunol Res. 2017;5(9):767-77. DOI:10.1158/2326-6066.CIR-16-0365
5. Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13(3):143-58. DOI:10.1038/nrclinonc.2015.209
6. Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021;18(4):842-59. DOI:10.1038/s41423-020-00565-9
7. Solomon B, Young RJ, Bressel M, et al. Prognostic significance of PD-L1(+) and CD8(+) immune cells in HPV(+) oropharyngeal squamous cell carcinoma. Cancer Immunol Res. 2018;6(3):295-304. DOI:10.1158/2326-6066.CIR-17-0299
8. Kushlinskii NE, Gershtein ES, Goryacheva IO, et al. Soluble ligand of the immune checkpoint receptor (sPD-L1) in blood serum of patients with renal cell carcinoma. Bulletin of Experimental Biology and Medicine. 2018;166(9):325-9 (in Russian).
9. Kovaleva OV, Gratchev AN, Makarova EI, et al. Prognostic significance of sPD-1/sPD-L1 in renal cancer depending on the phenotype of tumor and stromal cells. Onkourolog iya = Cancer Urology. 2022;18(2):17-28 (in Russian). DOI:10.17650/1726-9776-2022-18-2-17-28
10. Li X, Zheng Y, Yue F. Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in various cancers: A meta-analysis. Target Oncol. 2021;16(1):13-26.
DOI:10.1007/s11523-020-00763-5
11. Ruan Y, Hu W, Li W, et al. Analysis of plasma EBV-DNA and soluble checkpoint proteins in nasopharyngeal carcinoma patients after definitive intensity-modulated radiotherapy. BioMed Res Int. 2019;2019:3939720. DOI:10.1155/2019/3939720
12. Sorensen SF, Demuth C, Weber B, et al. Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib. Lung Cancer. 2016;100:77-84. DOI:10.1016/j.lungcan.2016.08.001
13. Bian B, Fanale D, Dusetti N, et al. Prognostic significance of circulating PD-1, PD‑L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma. Oncoimmunology. 2019;8(4):e1561120. DOI:10.1080/2162402x.2018.1561120
14. Xing YF, Zhang ZL, Shi MH, et al. The level of soluble programmed death-1 in peripheral blood of patients with lung cancer and its clinical implications. Zhonghua Jie He He Hu Xi Za Zhi. 2012;35(2):102-6 (in Chinese). PMID:22455965
15. Shi MH, Xing YF, Zhang ZL, et al. Effect of soluble PD-L1 released by lung cancer cells in regulating the function of T lymphocytes. Zhonghua Zhong Liu Za Zhi. 2013;35(2):85-8 (in Chinese). DOI:10.3760/cma.j.issn.0253-3766.2013.02.002
16. Zabotina TN, Chertkova AI, Borunova AA, et al. Relationship of lymphocyte subpopulations in breast cancer patients with treatment results. Rossiyskiy bioterapevticheskiy zurnal = Russian Journal of Biotherapy. 2021;20(3):25-33 (in Russian). DOI:10.17650/1726-9784-2021-20-3-25-33
17. Fiorentini S, Licenziati S, Alessandri G, et al. CD11b expression identifies CD8+CD28+ T lymphocytes with phenotype and function of both naive/memory and effector cells. J Immunol. 2001;166(2):900-7. DOI:10.4049/jimmunol.166.2.900
18. Caruso A, Fiorentini S, Licenziati S, et al. Expansion of rare CD8+ CD28- CD11b- T cells with impaired effector functions in HIV-1-infected patients. J Acquir Immune Defic Syndr.2000;24(5):465-74. DOI:10.1097/00126334-200008150-00012
19. Freedman MS, Ruijs TC, Blain M, Antel JP. Phenotypic and functional characteristics of activated CD8+ cells: a CD11b-CD28- subset mediates noncytolytic functional suppression. Clin Immunol Immunopathol. 1991;60(2):254-67. DOI:10.1016/0090-1229(91)90068-l
20. Beltra JC, Manne S, Abdel-Hakeem MS, et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. EJ Immunity. 2020;52(5):825-41. DOI:10.1016/j.immuni.2020.04.014
21. Schnell A, Schmidl C, Herr W, Siska PJ. The peripheral and intratumoral immune cell landscape in cancer patients: a proxy fort biology and a tool for outcome prediction. Biomedicines. 2018;6(1):25. DOI:10.3390/biomedicines6010025
22. Cillo AR, Kürten CHL, Tabib T, et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity. 2020;52(1):183-99.e9. DOI:10.1016/j.immuni.2019.11.014
23. Garaud S, Buisseret L, Solinas C, et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 2019;5(18):e129641. DOI:10.1172/jci.insight.129641
24. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549-55. DOI:10.1038/s41586-019-1922-8
25. Kadagidze ZG, Chertkova AI, Zabotina TN, et al. The relationship of markers of early and late lymphocytes activation with the effectiveness of neoadjuvant chemotherapy in patients with triple negative breast cancer with the effi ciency of neoadjuvant chemotherapy in triple negative breast cancer patients. Immunologiya = Immunology. 2021;42(2):112-24 (in Russian). DOI:10.33029/0206-4952-2021-42-2-112-124
26. McFarland HI, Nahill SR, Maciaszek JW, Welsh RM. CD11b (Mac-1): A marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992;149(4):1326-3310. PMID:1500720
27. Christensen JE, Andreasen SO, Christensen JP, Thomsen AR. CD11b expression as a marker to distinguish between recently activated effector CD8(+) T cells and memory cells. Int Immunol. 2001;13(4):593-600. DOI:10.1093/intimm/13.4.593
28. Marzagalli M, Ebelt ND, Manuel ER. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment. Semin Cancer Biol. 2019;59:236-50. DOI:10.1016/j.semcancer.2019.08.002
2. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol. 2020;1248:33-59. DOI:10.1007/978-981-15-3266-53
3. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111-22. DOI:10.1080/21645515.2019.1571892
4. Li HY, McSharry M, Bullock B, et al. The tumor microenvironment regulates sensitivity of murine lung tumors to PD-1/PD-L1 antibody blockade. Cancer Immunol Res. 2017;5(9):767-77. DOI:10.1158/2326-6066.CIR-16-0365
5. Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13(3):143-58. DOI:10.1038/nrclinonc.2015.209
6. Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021;18(4):842-59. DOI:10.1038/s41423-020-00565-9
7. Solomon B, Young RJ, Bressel M, et al. Prognostic significance of PD-L1(+) and CD8(+) immune cells in HPV(+) oropharyngeal squamous cell carcinoma. Cancer Immunol Res. 2018;6(3):295-304. DOI:10.1158/2326-6066.CIR-17-0299
8. Кушлинский Н.Е., Герштейн Е.С., Горячева И.О., и др. Растворимый лиганд рецептора контрольной точки иммунитета (sPD-L1) в сыворотке крови при почечно-клеточном раке. Бюллетень экспериментальной биологии и медицины. 2018;166(9):325-9 [Kushlinskii NE, Gershtein ES, Goryacheva IO, et al. Soluble ligand of the immune checkpoint receptor (sPD-L1) in blood serum of patients with renal cell carcinoma. Bulletin of Experimental Biology and Medicine. 2018;166(9):325-9 (in Russian)].
9. Ковалева О.В., Грачев А.Н., Макарова Э.И., и др. Прогностическая значимость sPD-1/sPD-L1 при раке почки в зависимости от фенотипа опухолевых и стромальных клеток. Онкоурология. 2022;18(2):17-28 [Kovaleva OV, Gratchev AN, Makarova EI, et al. Prognostic significance of sPD-1/sPD-L1 in renal cancer depending on the phenotype of tumor and stromal cells. Onkourolog iya = Cancer Urology. 2022;18(2):17-28 (in Russian)]. DOI:10.17650/1726-9776-2022-18-2-17-28
10. Li X, Zheng Y, Yue F. Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in various cancers: A meta-analysis. Target Oncol. 2021;16(1):13-26.
DOI:10.1007/s11523-020-00763-5
11. Ruan Y, Hu W, Li W, et al. Analysis of plasma EBV-DNA and soluble checkpoint proteins in nasopharyngeal carcinoma patients after definitive intensity-modulated radiotherapy. BioMed Res Int. 2019;2019:3939720. DOI:10.1155/2019/3939720
12. Sorensen SF, Demuth C, Weber B, et al. Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib. Lung Cancer. 2016;100:77-84. DOI:10.1016/j.lungcan.2016.08.001
13. Bian B, Fanale D, Dusetti N, et al. Prognostic significance of circulating PD-1, PD‑L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma. Oncoimmunology. 2019;8(4):e1561120. DOI:10.1080/2162402x.2018.1561120
14. Xing YF, Zhang ZL, Shi MH, et al. The level of soluble programmed death-1 in peripheral blood of patients with lung cancer and its clinical implications. Zhonghua Jie He He Hu Xi Za Zhi. 2012;35(2):102-6 (in Chinese). PMID:22455965
15. Shi MH, Xing YF, Zhang ZL, et al. Effect of soluble PD-L1 released by lung cancer cells in regulating the function of T lymphocytes. Zhonghua Zhong Liu Za Zhi. 2013;35(2):85-8 (in Chinese). DOI:10.3760/cma.j.issn.0253-3766.2013.02.002
16. Заботина Т.Н., Черткова А.И., Борунова А.А., и др. Взаимосвязь субпопуляций лимфоцитов больных раком молочной железы с результатами лечения. Российский биотерапевтический журнал. 2021;20(3):25-33 [Zabotina TN, Chertkova AI, Borunova AA, et al. Relationship of lymphocyte subpopulations in breast cancer patients with treatment results. Rossiyskiy bioterapevticheskiy zurnal = Russian Journal of Biotherapy. 2021;20(3):25-33 (in Russian)]. DOI:10.17650/1726-9784-2021-20-3-25-33
17. Fiorentini S, Licenziati S, Alessandri G, et al. CD11b expression identifies CD8+CD28+ T lymphocytes with phenotype and function of both naive/memory and effector cells. J Immunol. 2001;166(2):900-7. DOI:10.4049/jimmunol.166.2.900
18. Caruso A, Fiorentini S, Licenziati S, et al. Expansion of rare CD8+ CD28- CD11b- T cells with impaired effector functions in HIV-1-infected patients. J Acquir Immune Defic Syndr.2000;24(5):465-74. DOI:10.1097/00126334-200008150-00012
19. Freedman MS, Ruijs TC, Blain M, Antel JP. Phenotypic and functional characteristics of activated CD8+ cells: a CD11b-CD28- subset mediates noncytolytic functional suppression. Clin Immunol Immunopathol. 1991;60(2):254-67. DOI:10.1016/0090-1229(91)90068-l
20. Beltra JC, Manne S, Abdel-Hakeem MS, et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. EJ Immunity. 2020;52(5):825-41. DOI:10.1016/j.immuni.2020.04.014
21. Schnell A, Schmidl C, Herr W, Siska PJ. The peripheral and intratumoral immune cell landscape in cancer patients: a proxy fort biology and a tool for outcome prediction. Biomedicines. 2018;6(1):25. DOI:10.3390/biomedicines6010025
22. Cillo AR, Kürten CHL, Tabib T, et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity. 2020;52(1):183-99.e9. DOI:10.1016/j.immuni.2019.11.014
23. Garaud S, Buisseret L, Solinas C, et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 2019;5(18):e129641. DOI:10.1172/jci.insight.129641
24. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549-55. DOI:10.1038/s41586-019-1922-8
25. Кадагидзе З.Г., Черткова А.И., Заботина Т.Н., и др. Взаимосвязь маркеров ранней и поздней активации лимфоцитов с эффективностью неоадъювантной химиотерапии больных трижды негативным раком молочной железы. Иммунология. 2021;42(2):112-24 [Kadagidze ZG, Chertkova AI, Zabotina TN, et al. The relationship of markers of early and late lymphocytes activation with the effectiveness of neoadjuvant chemotherapy in patients with triple negative breast cancer with the effi ciency of neoadjuvant chemotherapy in triple negative breast cancer patients. Immunologiya = Immunology. 2021;42(2):112-24 (in Russian)]. DOI:10.33029/0206-4952-2021-42-2-112-124
26. McFarland HI, Nahill SR, Maciaszek JW, Welsh RM. CD11b (Mac-1): A marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992;149(4):1326-3310. PMID:1500720
27. Christensen JE, Andreasen SO, Christensen JP, Thomsen AR. CD11b expression as a marker to distinguish between recently activated effector CD8(+) T cells and memory cells. Int Immunol. 2001;13(4):593-600. DOI:10.1093/intimm/13.4.593
28. Marzagalli M, Ebelt ND, Manuel ER. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment. Semin Cancer Biol. 2019;59:236-50. DOI:10.1016/j.semcancer.2019.08.002
________________________________________________
2. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol. 2020;1248:33-59. DOI:10.1007/978-981-15-3266-53
3. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111-22. DOI:10.1080/21645515.2019.1571892
4. Li HY, McSharry M, Bullock B, et al. The tumor microenvironment regulates sensitivity of murine lung tumors to PD-1/PD-L1 antibody blockade. Cancer Immunol Res. 2017;5(9):767-77. DOI:10.1158/2326-6066.CIR-16-0365
5. Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13(3):143-58. DOI:10.1038/nrclinonc.2015.209
6. Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021;18(4):842-59. DOI:10.1038/s41423-020-00565-9
7. Solomon B, Young RJ, Bressel M, et al. Prognostic significance of PD-L1(+) and CD8(+) immune cells in HPV(+) oropharyngeal squamous cell carcinoma. Cancer Immunol Res. 2018;6(3):295-304. DOI:10.1158/2326-6066.CIR-17-0299
8. Kushlinskii NE, Gershtein ES, Goryacheva IO, et al. Soluble ligand of the immune checkpoint receptor (sPD-L1) in blood serum of patients with renal cell carcinoma. Bulletin of Experimental Biology and Medicine. 2018;166(9):325-9 (in Russian).
9. Kovaleva OV, Gratchev AN, Makarova EI, et al. Prognostic significance of sPD-1/sPD-L1 in renal cancer depending on the phenotype of tumor and stromal cells. Onkourolog iya = Cancer Urology. 2022;18(2):17-28 (in Russian). DOI:10.17650/1726-9776-2022-18-2-17-28
10. Li X, Zheng Y, Yue F. Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in various cancers: A meta-analysis. Target Oncol. 2021;16(1):13-26.
DOI:10.1007/s11523-020-00763-5
11. Ruan Y, Hu W, Li W, et al. Analysis of plasma EBV-DNA and soluble checkpoint proteins in nasopharyngeal carcinoma patients after definitive intensity-modulated radiotherapy. BioMed Res Int. 2019;2019:3939720. DOI:10.1155/2019/3939720
12. Sorensen SF, Demuth C, Weber B, et al. Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib. Lung Cancer. 2016;100:77-84. DOI:10.1016/j.lungcan.2016.08.001
13. Bian B, Fanale D, Dusetti N, et al. Prognostic significance of circulating PD-1, PD‑L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma. Oncoimmunology. 2019;8(4):e1561120. DOI:10.1080/2162402x.2018.1561120
14. Xing YF, Zhang ZL, Shi MH, et al. The level of soluble programmed death-1 in peripheral blood of patients with lung cancer and its clinical implications. Zhonghua Jie He He Hu Xi Za Zhi. 2012;35(2):102-6 (in Chinese). PMID:22455965
15. Shi MH, Xing YF, Zhang ZL, et al. Effect of soluble PD-L1 released by lung cancer cells in regulating the function of T lymphocytes. Zhonghua Zhong Liu Za Zhi. 2013;35(2):85-8 (in Chinese). DOI:10.3760/cma.j.issn.0253-3766.2013.02.002
16. Zabotina TN, Chertkova AI, Borunova AA, et al. Relationship of lymphocyte subpopulations in breast cancer patients with treatment results. Rossiyskiy bioterapevticheskiy zurnal = Russian Journal of Biotherapy. 2021;20(3):25-33 (in Russian). DOI:10.17650/1726-9784-2021-20-3-25-33
17. Fiorentini S, Licenziati S, Alessandri G, et al. CD11b expression identifies CD8+CD28+ T lymphocytes with phenotype and function of both naive/memory and effector cells. J Immunol. 2001;166(2):900-7. DOI:10.4049/jimmunol.166.2.900
18. Caruso A, Fiorentini S, Licenziati S, et al. Expansion of rare CD8+ CD28- CD11b- T cells with impaired effector functions in HIV-1-infected patients. J Acquir Immune Defic Syndr.2000;24(5):465-74. DOI:10.1097/00126334-200008150-00012
19. Freedman MS, Ruijs TC, Blain M, Antel JP. Phenotypic and functional characteristics of activated CD8+ cells: a CD11b-CD28- subset mediates noncytolytic functional suppression. Clin Immunol Immunopathol. 1991;60(2):254-67. DOI:10.1016/0090-1229(91)90068-l
20. Beltra JC, Manne S, Abdel-Hakeem MS, et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. EJ Immunity. 2020;52(5):825-41. DOI:10.1016/j.immuni.2020.04.014
21. Schnell A, Schmidl C, Herr W, Siska PJ. The peripheral and intratumoral immune cell landscape in cancer patients: a proxy fort biology and a tool for outcome prediction. Biomedicines. 2018;6(1):25. DOI:10.3390/biomedicines6010025
22. Cillo AR, Kürten CHL, Tabib T, et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity. 2020;52(1):183-99.e9. DOI:10.1016/j.immuni.2019.11.014
23. Garaud S, Buisseret L, Solinas C, et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 2019;5(18):e129641. DOI:10.1172/jci.insight.129641
24. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549-55. DOI:10.1038/s41586-019-1922-8
25. Kadagidze ZG, Chertkova AI, Zabotina TN, et al. The relationship of markers of early and late lymphocytes activation with the effectiveness of neoadjuvant chemotherapy in patients with triple negative breast cancer with the effi ciency of neoadjuvant chemotherapy in triple negative breast cancer patients. Immunologiya = Immunology. 2021;42(2):112-24 (in Russian). DOI:10.33029/0206-4952-2021-42-2-112-124
26. McFarland HI, Nahill SR, Maciaszek JW, Welsh RM. CD11b (Mac-1): A marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992;149(4):1326-3310. PMID:1500720
27. Christensen JE, Andreasen SO, Christensen JP, Thomsen AR. CD11b expression as a marker to distinguish between recently activated effector CD8(+) T cells and memory cells. Int Immunol. 2001;13(4):593-600. DOI:10.1093/intimm/13.4.593
28. Marzagalli M, Ebelt ND, Manuel ER. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment. Semin Cancer Biol. 2019;59:236-50. DOI:10.1016/j.semcancer.2019.08.002
Авторы
Т.Н. Заботина*, А.И. Черткова, А.А. Борунова, Н.Е. Кушлинский, Е.С. Герштейн, Е.Н. Захарова, Э.К. Шоуа, В.Т. Циклаури, И.В. Самойленко, М.В. Хорошилов, З.Г. Кадагидзе
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия
*tatzabotina@yandex.ru
Blokhin National Medical Research Center of Oncology, Moscow, Russia
*tatzabotina@yandex.ru
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия
*tatzabotina@yandex.ru
________________________________________________
Blokhin National Medical Research Center of Oncology, Moscow, Russia
*tatzabotina@yandex.ru
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