Comprehensive assessment of the systemic and local immunity, inflammatory factors and clinical indicators in patients with gastric cancer
https://doi.org/10.18027/2224-5057-2020-10-4-5-15
Abstract
Objective.To study the state of cellular immunity and local immunity in patients with gastric adenocarcinoma.
Materials and methods.From 2017 to 2018 45 primary patients with gastric adenocarcinoma (25 — with stages I–III, 20 — with stage IV) received surgical / combined treatment or chemotherapy at the Blokhin Scientific Research Center of Oncology, respectively. Peripheral blood and tumor tissue were collected before starting treatment. The percentage of the degree of infiltration of tumor tissue by lymphocytes (CD45 + CD14‑TILs) was assessed by flow cytometry: T‑cells (CD3 + CD19‑TILs), B‑cells (CD3‑CD19 + TILs), NK‑cells (CD3‑CD16 + CD56 + TILs), effector cells CD16 and CD8 and their cytotoxic potential (CD16 + Perforin + TILs, CD16CTPTILs), (CD8 + Perforin + TILs; CD8CTPTILs); subpopulations of regulatory T‑cells — NKT‑cells (CD3 + CD16 + CD56 + TILs), regulatory CD4‑cells (CD4 + CD25 + CD127‑TILs) and CD8 (CD8 + CD11b‑CD28‑TILs) and parameters of systemic immunity.
Intratumoral and stromal subpopulations of CD4 + TILs, CD8 + TILs, CD4 + / CD8 + TILs ratios were studied by immunohistochemistry. Also, the cellular composition of peripheral blood was investigated. The prognostic significance of immune cells, inflammation factors (neutrophil‑lymphocyte index, platelet‑lymphocyte index) and clinical characteristics (patient»s age (both by years and by groups: up to 45 years, 46–60 years, over 60 years), disease stage, differentiation (G), Lauren type and MSI status were evaluated for overall survival (OS) and progression‑free survival (PFS).
Results.The factor of a favorable prognosis for PFS in patients with local and locally advanced forms of gastric cancer was an increase in the number of CD3 + CD19‑TILs (HR0.865, 95 %CI 0.782–0.957, p = 0.005), and for poor prognosis — an increase in NK‑cells; HR1.382, 95 %CI 1.087–1.758, p = 0.008. There was a negative effect of the relative content of NK‑cells, an increase in the level of neutrophils in the peripheral blood on the OS of patients with metastatic GC (HR1.42, 95 %CI 1.06–1.89, p = 0.017 and HR1.64, 95 %CI 1.12–2.40, p = 0.011). At the same time, an increase in the age of patients, the level of neutrophils and platelets (HR1.106, 95 %CI 1.002–1.199, p = 0.015; HR1.714, 95 %CI 1.063–2.764, p = 0.027 and HR1.017, 95 %CI 1.006–1.029, p = 0.003) reduce PFS in patients with metastatic gastric cancer.
Conclusion.Indicators of local immunity, the cellular composition of peripheral blood, characterizing the systemic inflammatory response, as well as indicators of systemic immunity can serve as additional prognostic factors in gastric cancer.
About the Authors
G. G. KhakimovaUzbekistan
Gulnoz G. Khakimova, MD, PhD, oncologist
Tashkent
A. A. Tryakin
Russian Federation
Alexey A. Tryakin, MD, PhD, DSc, Head of the Oncology Department Drug Methods of Treatment (chemotherapy)
Moscow
T. N. Zabotina
Russian Federation
Tatyana N. Zabotina, MD, DSC Biol, Head of the Department of Clinical and Laboratory Diagnostics
Moscow
Sh. G. Khakimova
Uzbekistan
Shakhnoz G. Khakimova, MD, PhD
Moscow
References
1. Бережная Н. М. Взаимодействие клеток системы иммунитета с другими компонентами микроокружения. Онкология. 2009; 1 (2): 86–93.
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 молочнойжелезы. В кн.: Рак молочнойжелезы. Под ред. Н. Е. Кушлинского, С.М. Портного, К. П. Лактионова. М.: Издательство РАМН, 2005; с. 174–97.
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. Zamarron B. F., Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011; 7 (5): 651–658.
7. Ruffell B., DeNardo D. G., Affara N. I. et al. Lymphocytes in cancer development: polarization towards protumor immunity. Cytokine Growth Factor Rev. 2010; 21: 3–10.
8. Shen Z. Zhou S., Wang Y. et al. Higher intratumoral infiltrated Foxp3 + Treg numbers and Foxp3 + / C8 + ratio are associated with adverse prognosis in resectable gastric cancer. J Cancer Res Clin. Oncol. 2010; 136:1585–1595.
9. Mori M., Shuto K., Kosugi C. et al. An increase in the neutrophil to lymphocyte ratio during adjuvant chemotherapy indicates a poor prognosis in patients with stage II or III gastric cancer. BMC Cancer. 2018;18 (1):1261.
10. Passardi A., Scarpi E., Cavanna L. et al. Inflammatory indexes as predictors of prognosis and bevacizumab efficacy in patients with metastatic colorectal cancer. Oncotarget 2016;7 (22):33210–9. DOI: 10.18632 / oncotarget. 8901.
11. Gunaldi M., Goksu S., Erdem D. et al. Prognostic impact of platelet / lymphocyte and neutrophil / lymphocyte ratios in patients with gastric cancer: a multicenter study. Int J Clin Exp Med. 2015;8 (4):5937–42.
12. Zheng X., Song X., Shao Y. et al. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: A meta-analysis. Oncotarget. 2017; 8. 10.18632 / oncotarget. 18065.
13. Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014; 513: 202–209.
14. Müller P., Rothschild S. I., 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.
15. 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.
16. Huszno J., Nożyńska E. Z., 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.
17. 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).
18. 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 tumor in patients with gastric carcinoma. Eur J of Cancer 1991; 27 (12): 1654–7 / 19. 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.
19. 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.
20. Peng L. S., Mao F. Y., Zhao Y. L. 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
21. Takeuchi H., Maehara Y., Tokunaga E. 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.
Review
For citations:
Khakimova G.G., Tryakin A.A., Zabotina T.N., Khakimova Sh.G. Comprehensive assessment of the systemic and local immunity, inflammatory factors and clinical indicators in patients with gastric cancer. Malignant tumours. 2020;10(4):5-15. (In Russ.) https://doi.org/10.18027/2224-5057-2020-10-4-5-15