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Влияние локального иммунитета на прогноз рака желудка
Хакимова Г.Г., Трякин А.А., Заботина Т.Н. и др. Влияние локального иммунитета на прогноз рака желудка. Современная Онкология. 2020; 22 (1): 36–41. DOI: 10.26442/18151434.2020.1.200049
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Khakimova G.G., Tryakin A.A., Zabotina T.N. et al. The effect of local immunity on gastric cancer prognosis. Journal of Modern Oncology. 2020; 22 (1): 36–41. DOI: 10.26442/18151434.2020.1.200049
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Аннотация
Цель. Изучить состояние локального иммунитета у больных аденокарциномой желудка.
Материалы и методы. С 2017 по 2018 г. в ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» 45 ранее нелеченных больных аденокарциномой желудка (25 – с I–III стадиями, 20 – с IV стадией) получили хирургическое/комбинированное лечение или химиотерапию, соответственно. Забор опухолевой ткани осуществлялся перед началом лечения. Методом проточной цитометрии оценивалось процентное содержание степени инфильтрации опухолевой ткани лимфоцитами (CD45+CD14-TIL); Т-клеток (CD3+CD19-TIL); В-клеток (CD3-CD19+TIL); NK-клеток (CD3-CD16+CD56+TIL); эффекторных клеток CD16 (CD16+Perforin+TIL) и CD8 (CD8+Perforin+TIL) и их цитотоксического потенциала – active CD16TIL и active CD8TIL; субпопуляций регуляторных Т-клеток – NKT-клеток (CD3+CD16+CD56+TIL), регуляторных клеток CD4 (CD4+CD25+CD127-TIL) и CD8 (CD8+CD11b-CD28-TIL). Проведена оценка прогностической значимости иммунных клеток для общей выживаемости (ОВ) и выживаемости без прогрессирования (ВБП).
Результаты. Фактором благоприятного прогноза в отношении ВБП у пациентов с локальными и местно-распространенными формами рака желудка явилось повышение числа CD3-CD19+TIL (отношение рисков – ОР 0,862, 95% доверительный интервал – ДИ 0,782–0,957, р=0,005), а неблагоприятного прогноза – повышение NK-клеток (CD3-CD16+CD56+TIL); ОР 1,382, 95% ДИ 1,087–1,758, р=0,008. Отмечено негативное влияние относительного содержания NK-клеток (CD3-CD16+CD56+TIL) и NKТ-клеток (CD3+CD16+CD56+TIL) на ОВ пациентов с метастатическим раком желудка (ОР 1,249, 95% ДИ 0,997–1,564, р=0,053 и ОР 1,127, 95% ДИ 1,025–1,239, р=0,013). В то же время увеличение процентного содержания инфильтрации опухолевой ткани лимфоцитами (CD45+CD14-TIL) и увеличение возраста больных (ОР 1,005, 95% ДИ 1,002–1,008, р=0,003 и ОР 1,098, 95% ДИ 1,031–1,170, р=0,004) – снижают показатель ВБП у пациентов с метастатическим раком желудка.
Вывод. Показатели локального иммунитета могут служить дополнительными прогностическими факторами при раке желудка.
Ключевые слова: аденокарцинома желудка, локальный иммунитет, субпопуляции лимфоцитов.
Материалы и методы. С 2017 по 2018 г. в ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» 45 ранее нелеченных больных аденокарциномой желудка (25 – с I–III стадиями, 20 – с IV стадией) получили хирургическое/комбинированное лечение или химиотерапию, соответственно. Забор опухолевой ткани осуществлялся перед началом лечения. Методом проточной цитометрии оценивалось процентное содержание степени инфильтрации опухолевой ткани лимфоцитами (CD45+CD14-TIL); Т-клеток (CD3+CD19-TIL); В-клеток (CD3-CD19+TIL); NK-клеток (CD3-CD16+CD56+TIL); эффекторных клеток CD16 (CD16+Perforin+TIL) и CD8 (CD8+Perforin+TIL) и их цитотоксического потенциала – active CD16TIL и active CD8TIL; субпопуляций регуляторных Т-клеток – NKT-клеток (CD3+CD16+CD56+TIL), регуляторных клеток CD4 (CD4+CD25+CD127-TIL) и CD8 (CD8+CD11b-CD28-TIL). Проведена оценка прогностической значимости иммунных клеток для общей выживаемости (ОВ) и выживаемости без прогрессирования (ВБП).
Результаты. Фактором благоприятного прогноза в отношении ВБП у пациентов с локальными и местно-распространенными формами рака желудка явилось повышение числа CD3-CD19+TIL (отношение рисков – ОР 0,862, 95% доверительный интервал – ДИ 0,782–0,957, р=0,005), а неблагоприятного прогноза – повышение NK-клеток (CD3-CD16+CD56+TIL); ОР 1,382, 95% ДИ 1,087–1,758, р=0,008. Отмечено негативное влияние относительного содержания NK-клеток (CD3-CD16+CD56+TIL) и NKТ-клеток (CD3+CD16+CD56+TIL) на ОВ пациентов с метастатическим раком желудка (ОР 1,249, 95% ДИ 0,997–1,564, р=0,053 и ОР 1,127, 95% ДИ 1,025–1,239, р=0,013). В то же время увеличение процентного содержания инфильтрации опухолевой ткани лимфоцитами (CD45+CD14-TIL) и увеличение возраста больных (ОР 1,005, 95% ДИ 1,002–1,008, р=0,003 и ОР 1,098, 95% ДИ 1,031–1,170, р=0,004) – снижают показатель ВБП у пациентов с метастатическим раком желудка.
Вывод. Показатели локального иммунитета могут служить дополнительными прогностическими факторами при раке желудка.
Ключевые слова: аденокарцинома желудка, локальный иммунитет, субпопуляции лимфоцитов.
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Aim. To study the state of local immunity in patients with gastric adenocarcinoma.
Materials and methods. From 2017 to 2018, 45 previously untreated patients with gastric adenocarcinoma (25 with stage I–III,
20 with stage IV) received surgical/combined treatment or chemotherapy, respectively, at the Blokhin Scientific Research Center of Oncology. Tumor tissue was taken before treatment. By using flow cytometry there were evaluated the percentage of tumor tissue infiltration by lymphocytes (CD45+CD14-TIL); T cells (CD3+CD19-TIL); B cells (CD3-CD19+TIL); NK cell (CD3-CD16+CD56+TIL); effector cells CD16 (CD16+Perforin+TIL) and CD8 (CD8+Perforin+TIL) with their cytotoxic potential – active CD16TIL and active CD8TIL; subpopulations of regulatory T cells – NKT cells (CD3+CD16+CD56+TIL), regulatory cells CD4 (CD4+CD25+CD127-TIL) and CD8 (CD8+CD11b-CD28-TIL). The prognostic value of immune cells for overall survival (OS) and progression-free survival (PFS) was assessed.
Results. A favorable prognosis factor for progression-free survival in patients with local and locally advanced forms of gastric cancer was an increase in the number of CD3-CD19+TIL (HR 0.862, 95% CI 0.782–0.957, p=0.005), and an unfavorable prognosis was an increase in NK cells (CD3-CD16+CD56+TIL); HR 1.382, 95% CI 1.087–1.758, p=0.008. The negative effect of the relative content of NK cells (CD3-CD16+CD56+TIL) and NKT cells (CD3+CD16+CD56+TIL) on OS of patients with metastatic gastric cancer noted (HR 1.249, 95% CI 0.997–1.564, p=0.053; HR 1.127, 95% CI 1.025–1.239, p=0.013). At the same time, an increase in the percentage of tumor tissue infiltration by lymphocytes (CD45+CD14-TIL) and an increase in the age of patients (HR 1.005, 95% CI 1.002–1.008, p=0.003; HR 1.098, 95% CI 1.031–1.170, p=0.004) reduce the incidence of PFS in patients with metastatic gastric carcinoma.
Conclusion. Indices of local immunity can serve as additional prognostic factors for gastric carcinoma.
Key words: gastric adenocarcinoma, local immunity, subpopulations of lymphocytes.
Полный текст
Список литературы
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[Berezhnaia N.M. Vzaimodeĭstvie kletok sistemy immuniteta s drugimi komponentami mikrookruzheniia. Onkologiia. 2009; 1 (2): 86–93 (in Russian).]
2. Mantovani A et al. Tumor immunity: effector response to tumor and role of the microenvironment. Lancet 2008; 371 (9614): 771–83.
3. Тупицын Н.Н. Иммунофенотип рака молочной железы. В кн.: Рак молочной железы. Под ред. Н.Е. Кушлинского, С.М. Портного, К.П. Лактионова. М.: Издательство РАМН, 2005; с. 174–97.
[Tupitsyn N.N. Immunofenotip raka molochnoĭ zhelezy. V kn.: Rak molochnoĭ zhelezy. Pod red. N.E. Kushlinskogo, S.M. Portnogo, K.P. Laktionova. Moscow: Izdatel'stvo RAMN, 2005; p. 174–97 (in Russian).]
4. Balch C, Riley L, Bae T et al. Patterns of human tumor infiltrating lymphocytes in 120 human cancers. Arch Surg 1990; 125 (2): 200–5.
5. Galon J, Pages F et al. Cancer classification using the immunoscore: a worldwide task force. J Transl Med 2012; 10: 205.
6. Ali HR, Provenzano E, Dawson SJ et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 2014; 25 (8): 1536–43.
7. Ladányi A. Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res 2015. DOI: 10.1111/pcmr.12371
8. Sconocchia G et al. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology 2014; 3 (8): e952197.
9. D’Angelo SP et al. Prevalence of tumor-infiltrating lymphocytes and
PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol 2015; 46 (3): 357–65. DOI: 10.1016/j. humpath.2014.11.001
10. Djenidi F et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognos- tic factor for survival in lung cancer patients. J Immunol 2015; 194 (7): 3475–86. DOI: 10.4049/jimmunol.1402711
11. Xiao Zheng, Xing Song, Yingjie Shao et al. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A meta-analysis. Oncotarget. 2017; 8. 10.18632/oncotarget.18065.
12. Müller P, Rothschild SI, Arnold W et al. Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells. Cancer Immunol Immunother 2016; 65: 1–1.
13. Kollmann D, Ignatova D, Jedamzik J et al. Expression of programmed cell death protein 1 by tumor-infiltrating lymphocytes and tumor cells is associated with advanced tumor stage in patients with esophageal adenocarcinoma. Ann Surg Oncol 2017; 24: 2698–706.
14. Huszno J, Nożyńska EZ, Lange D et al. The association of tumor lymphocyte infiltration with clinicopathological factors and survival in breast cancer. Pol J Pathol 2017; 68: 26–32.
15. Lu J, Xu Y, Wu Y et al. Tumor-infiltrating CD8+ T cells combined with tumor-associated CD68+ macrophages predict postoperative prognosis and adjuvant chemotherapy benefit in resected gastric cancer. BMC Cancer 2019; 920 (19).
16. Ebihara T, Sakai N, Koyama S. Suppression by sorted CD8+CD11b-cells from T-cell growth factor-activated peripheral blood lymphocytes on cytolytic activity against tumour in patients with gastric carcinoma. Eur J of Cancer 1991; 27 (12): 1654–7/
17. Hou J, Yu Z, Xiang R et al. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Molecular Pathol 2014; 96 (3): 284–91.
18. Yuan X-L, Chen L, Li M-X et al. Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin Immunol 2010; 134 (3): 277–88.
19. Peng LS, Mao FY, Zhao YL et al. Altered phenotypic and functional characteristics of CD3+CD56+ NKT-like cells in human gastric cancer. Oncotarget 2016; 7 (34): 55222–30. DOI: 10.18632/oncotarget.10484
20. Hideya Takeuchi, Yoshihiko Maehara, Eriko Tokunaga et al. Prognostic Significance of Natural Killer Cell Activity in Patients With Gastric Carcinoma: A Multivariate Analysis. Am J Gastroenterol 2001; 96 (2): 574–8.
________________________________________________
1. Berezhnaia N.M. Vzaimodeĭstvie kletok sistemy immuniteta s drugimi komponentami mikrookruzheniia. Onkologiia. 2009; 1 (2): 86–93 (in Russian).
2. Mantovani A et al. Tumor immunity: effector response to tumor and role of the microenvironment. Lancet 2008; 371 (9614): 771–83.
3. Tupitsyn N.N. Immunofenotip raka molochnoĭ zhelezy. V kn.: Rak molochnoĭ zhelezy. Pod red. N.E. Kushlinskogo, S.M. Portnogo, K.P. Laktionova. Moscow: Izdatel'stvo RAMN, 2005; p. 174–97 (in Russian).
4. Balch C, Riley L, Bae T et al. Patterns of human tumor infiltrating lymphocytes in 120 human cancers. Arch Surg 1990; 125 (2): 200–5.
5. Galon J, Pages F et al. Cancer classification using the immunoscore: a worldwide task force. J Transl Med 2012; 10: 205.
6. Ali HR, Provenzano E, Dawson SJ et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 2014; 25 (8): 1536–43.
7. Ladányi A. Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res 2015. DOI: 10.1111/pcmr.12371
8. Sconocchia G et al. NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology 2014; 3 (8): e952197.
9. D’Angelo SP et al. Prevalence of tumor-infiltrating lymphocytes and
PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol 2015; 46 (3): 357–65. DOI: 10.1016/j. humpath.2014.11.001
10. Djenidi F et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognos- tic factor for survival in lung cancer patients. J Immunol 2015; 194 (7): 3475–86. DOI: 10.4049/jimmunol.1402711
11. Xiao Zheng, Xing Song, Yingjie Shao et al. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A meta-analysis. Oncotarget. 2017; 8. 10.18632/oncotarget.18065.
12. Müller P, Rothschild SI, Arnold W et al. Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells. Cancer Immunol Immunother 2016; 65: 1–1.
13. Kollmann D, Ignatova D, Jedamzik J et al. Expression of programmed cell death protein 1 by tumor-infiltrating lymphocytes and tumor cells is associated with advanced tumor stage in patients with esophageal adenocarcinoma. Ann Surg Oncol 2017; 24: 2698–706.
14. Huszno J, Nożyńska EZ, Lange D et al. The association of tumor lymphocyte infiltration with clinicopathological factors and survival in breast cancer. Pol J Pathol 2017; 68: 26–32.
15. Lu J, Xu Y, Wu Y et al. Tumor-infiltrating CD8+ T cells combined with tumor-associated CD68+ macrophages predict postoperative prognosis and adjuvant chemotherapy benefit in resected gastric cancer. BMC Cancer 2019; 920 (19).
16. Ebihara T, Sakai N, Koyama S. Suppression by sorted CD8+CD11b-cells from T-cell growth factor-activated peripheral blood lymphocytes on cytolytic activity against tumour in patients with gastric carcinoma. Eur J of Cancer 1991; 27 (12): 1654–7/
17. Hou J, Yu Z, Xiang R et al. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Molecular Pathol 2014; 96 (3): 284–91.
18. Yuan X-L, Chen L, Li M-X et al. Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin Immunol 2010; 134 (3): 277–88.
19. Peng LS, Mao FY, Zhao YL et al. Altered phenotypic and functional characteristics of CD3+CD56+ NKT-like cells in human gastric cancer. Oncotarget 2016; 7 (34): 55222–30. DOI: 10.18632/oncotarget.10484
20. Hideya Takeuchi, Yoshihiko Maehara, Eriko Tokunaga et al. Prognostic Significance of Natural Killer Cell Activity in Patients With Gastric Carcinoma: A Multivariate Analysis. Am J Gastroenterol 2001; 96 (2): 574–8.
Авторы
Г.Г. Хакимова*, А.А. Трякин, Т.Н. Заботина, А.А. Борунова, О.А. Малихова, Ф.М. Джураев, И.Н. Перегородиев, Е.Н. Захарова, Д.В. Табаков
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия
*hgg_doc@mail.ru
ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия
*hgg_doc@mail.ru
________________________________________________
Gulnoz G. Khakimova*, Alexey A. Tryakin, Tatyana N. Zabotina, Anna A. Borunova, Olga A. Malikhova, Farruh M. Juraev, Ivan N. Peregorodiev, Elena N. Zaharova, Dmitriy V. Tabakov
Blokhin National Medical Research Center of Oncology, Moscow, Russia
*hgg_doc@mail.ru
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