The identification of tumor-infiltrating lymphocytes in patients with stomach cancer

Cover Page

Cite item

Full Text

Abstract

Background. Stomach cancer (SC) is the 6th most common neoplasm among cancers (1 033 701 cases; 5.7%) and the 3rd most deadly cancer worldwide for men and women (782 685 deaths, 8.2%). SC therapy is a complex treatment associated with surgery, adjuvant chemotherapy, targeted therapy and immunotherapy with checkpoint inhibitors, nowadays. Despite the fact that the SC understanding has significantly increased within recent years, the prognosis still remains poor. In addition, very often the patients with the same stage of SC according to the international TNM classification of malignant tumors have different overall survival. Therefore, in order to improve survival rates, is necessary to understand the mechanisms of disease progression and to find new effective predictive factors. Besides many SC predictive factors, such as clinical and morphological characteristics (Lauren histologic type of tumor, degree of differentiation), biomarkers, deficient mismatch repair (dMMR), we have also revealed the positive correlation between the degree of tumor infiltration of tumor-infiltrating lymphocytes (TILs), especially with the spatial location of cell types (intratumoral or stromal cells), and the survival indicators of the patients with malignant neoplasms, recently. Moreover, TILs are the most significant predictive factors in patient survival rates than the TNM classification. At the same time, TILs predictive role in SC is still not clearly defined. Thus, the understanding of the degree of tumor infiltration of TILs depending on the spatial location would allow to determine the predictive significance, as well as to determine the direction of the immune reactions generating in patients with SC at the tissue level, depending on the risk and probability of progression.

Aim. To study the predictive significance of intratumoral and stromal CD4+TILs, CD8+TILs and CD4+/CD8+TILs in patients with gastric adenocarcinoma.

Materials and methods. From 2017 to 2018, 45 previously untreated patients with gastric adenocarcinoma (25 patients with stages I–III, 20 patients with stage IV) received surgical/combined treatment or independent chemotherapy, respectively, at the Blokhin National Medical Research Center of Oncology. The histological material was carried out before the treatment. Intratumoral (iTILs) and stromal (sTILs) values of CD4+TILs, CD8+TILs, CD4/CD8+TILs and the predictive significance in respect of overall survival and progression-free survival (PFS) were studied.

Results. During the observation period (16.4±6.2 months) CD4+/CD8+iTILs were factors of poor prognosis concerning PFS in patients of the first group (p=0.035; odds ratio – OR 3.264, 95% confidence interval – CI). We also identified the statistically significant decrease in CD4+iTILs, CD8+iTILs, CD4+/CD8+iTILs and the absence of CD4+sTILs, CD8+sTILs, CD4+/CD8+sTILs in patients with metastatic SC (р=0.0003; р=0.000004; р=0.00001).

Conclusion. The results show the positive predictive significance of CD4+sTILs, CD8+sTILs, CD4+/CD8+sTILs. At the same time, the increase of CD4+/CD8+iTILs reduces the PFS in patients with early and locally advanced SC.

About the authors

Gulnoz G. Khakimova

Tashkent Pediatric Medical Institute

Author for correspondence.
Email: hgg_doc@mail.ru
ORCID iD: 0000-0002-4970-5429

Cand. Sci. (Med.)

Uzbekistan, Tashkent

Yana A. Bozhchenko

Blokhin National Medical Research Center of Oncology

Email: hgg_doc@mail.ru

Cand. Sci. (Med.)

Russian Federation, Moscow

Tatyana N. Zabotina

Blokhin National Medical Research Center of Oncology

Email: tatzabotina@yandex.ru
ORCID iD: 0000-0001-7631-5699

D. Sci. (Biol.)

Russian Federation, Moscow

Alexey A. Tryakin

Blokhin National Medical Research Center of Oncology

Email: hgg_doc@mail.ru

D. Sci. (Med.)

Russian Federation, Moscow

References

  1. Каприн А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2018 г. М., 2019 [Kaprin AD, Starinskii VV, Petrova GV. Zlokachestvennye novoobrazovaniia v Rossii v 2018 g. Moscow, 2019 (in Russian)].
  2. Yazici O, Sendur MA, Ozdemir N, Aksoy S. Targeted therapies in gastric cancer and future perspectives. W J Gastroenterol. 2016;22(2):41-89.
  3. Waddell T, Verheij M, Allum W, et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013:24(Suppl. 6):57-63.
  4. Okines AF, Norman AR, McCloud P, et al. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol. 2009;20:1529-34.
  5. Никулин М.П., Сельчук В.Ю. Рак желудка. Рус. мед. журн. 2003;26(11):1441-9 [Nikulin MP, Selchuk VIu. Gastric cancer. RMZh. 2003;26(11):1441-9 (in Russian)].
  6. Kim JS, Kim MA, Kim TM, et al. Biomarker analysis in stage III–IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival. Br J Cancer. 2009;100:732-8.
  7. McCarty WC. Principles of prognosis in cancer. JAMA. 1931;96:30-3.
  8. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565-70.
  9. Al-Shibli K, Al-Saad S, Donnem T, et al. The prognostic value of intraepithelial and stromal innate immune system cells in non-small cell lung carcinoma. Histopathology. 2009;55:301-12.
  10. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610-8.
  11. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949-55.
  12. Mackensen A, Ferradini L, Carcelain G, et al. Evidence for in situ amplification of cytotoxic T-lymphocytes with antitumor activity in a human regressive melanoma. Cancer Res. 1993;53:3569-73.
  13. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203-13.
  14. Fukunaga A, Miyamoto M, Cho Y, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28:e26-31.
  15. Kawai O, Ishii G, Kubota K, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer. 2008;113:1387-95.
  16. Goc J, Germain C, Vo-Bourgais TK, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74:705-15.
  17. Бережная Н.М. Взаимодействие клеток системы иммунитета с другими компонентами микроокружения. Онкология. 2009;1(2):86-93 [Berezhnaya NM. Role of immune system cells in tumor microenvironment. II. Interaction of the immune system cells with other microenvironment components. Oncology. 2009;1(2):86-93 (in Russian)].
  18. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;6917(420):860-7.
  19. Takenaka Y, Oya R, Kitamiura T, et al. Platelet count and platelet-lymphocyte ratio as prognostic markers for head and neck squamous cell carcinoma: Meta-analysis. Head Neck. 2018;40(12):2714-23.
  20. Lee JS, Won HS, Sun S, et al. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer:A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(32):е.11769.
  21. 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;136:1585-95.
  22. Kang BW, Seo AN, Yoon S, et al. Prognostic value of tumor-infiltrating lymphocytes in Epstein–Barr virus-associated gatric cancer. Ann Oncol. 2016;27:494-501.
  23. Grogg KL, Lohse CM, Pankratz VS, et al. Lymphocyte-rich gastric cancer:ssociations with Epstein–Barr virus, microsatellite instability, histology, and survival. Mod Pathol. 2003;16(7):641-51.
  24. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259-71.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Immunohistochemical (IHC) study of the degree of tumor infiltration of CD8+ T-lymphocytes into stomach cancer (SC) lymphoid infiltration: a – intratumoral tumor lymphocyte infiltration (×40); b – peritumoral tumor lymphocyte infiltration (×20).

Download (195KB)
Indexing metadata
3. Fig. 2. IHC-analysis of the degree of tumor infiltration of CD4+ T-lymphocytes into SC lymphoid infiltration: a – intratumoral tumor lymphocyte infiltration (×20); b – intratumoral tumor lymphocyte infiltration (×10).

Download (173KB)
Indexing metadata
4. Fig. 3. The correlation between CD4+TILs, CD8+TILs and CD4+/CD8+TILs depending on the distribution of immune cells.

Download (77KB)
Indexing metadata
5. Fig. 4. Overall survival and progression-free survival in patients of the first and second groups.

Download (100KB)
Indexing metadata

Copyright (c) 2021 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies