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Experimental and Clinical Gastroenterology

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Assesment of changes in the pattern of immune cell infi ltrate subpopulation in syngeneic MC38 colorectal cancer during course administration of glutamyltryptophan: an experimental study

https://doi.org/10.31146/1682-8658-ecg-244-12-163-176

Abstract

Despite advances in gastric cancer screening and therapy, the search for effective methods for treating and preventing precancerous conditions, including chronic atrophic gastritis, remains an important challenge. Immunoprevention of cancer occupies a special place among strategies aimed at reducing the incidence of malignant neoplasms. The aim of this study was to assess changes in the subpopulation composition of the immune infiltrate in a syngeneic tumor model during course administration of glutamyl-tryptophan in mice. Materials and Methods. Tumor material was obtained from syngeneic MC38 colorectal cancer cells, transplanted intramammarily. Experimental animals received glutamyl-tryptophan (0.02 mg/kg), while control animals received saline. Repeated administrations were performed starting 14 days prior to tumor transplantation and continued until day 14 or day 21 after transplantation. Tumor growth kinetics and the subpopulation composition of the tumor immune infiltrate were assessed using flow cytometry. Results. Glutamyl-tryptophan administration did not affect tumor growth, but altered the cellular composition of the immune infiltrate at the second time point, manifested as a decrease in CD45+ cells, an increase in CD3+ cells, and a reduction in M2-like macrophages with high MHC expression. Analysis of DN-cell subpopulations at both time points demonstrated an increase in DN cells in both groups. In controls, DN NK+ cells decreased twofold, whereas no such decrease was observed in the experimental group. Reduced levels of CD3+CD8+ and NK1.1+ cells in both groups confirmed tumor progression. In contrast to the experimental group, the control group exhibited a pronounced decline in CD3+, MHC II low CD206+, and DN NK1.1+ cells, which may indicate a transition of the tumor microenvironment toward an immunosuppressive state. Conclusion. For the first time, changes in the composition of the immune infiltrate were evaluated in a model of a transplantable syngeneic tumor in immunocompetent animals treated with glutamyl-tryptophan. The study identified potential effector cell populations responsible for mediating immunosurveillance of tumor promotion and progression under in vivo experimental conditions.

About the Authors

S. A. Savelyev
JSCo Cytomed
Russian Federation


Ya. G. Murazov
Scientific Production Association “Home of Pharmacy”
Russian Federation


P. P. Beltiukov
Research Institute of Hygiene, Occupational Pathology and Human Ecology
Russian Federation


N. V. Baryshnikova
St. Petersburg State Pediatric Medical University
Russian Federation


S. V. Petlenko
S.N. Golikov Research Clinical Center of Toxicology
Russian Federation


References

1. Miao Q., Qin B., Piao S., Ma C. Global research trends on the association between gastric cancer and chronic atrophic gastritis: a bibliometric analysis. Discov Oncol. 2025;16(1):1603. doi: 10.1007/s12672-025-03392-4.

2. Sui Z., Chen J., Li P., Shao L. et al. Risk for gastric cancer in patients with gastric atrophy: a systematic review and meta-analysis. Transl Cancer Res. 2020; 9(3): 1618-1624. doi: 10.21037/tcr.2020.01.54.

3. Bray F., Laversanne M., Sung H. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi: 10.3322/caac.21834.

4. Shao-hua Z., Lin-lin R., Shen S., Yun-he T. et al. Atrophic gastritis rather than Helicobacter pylori infection can be an independent risk factor of colorectal polyps: a retrospective study in China. BMC Gastroenterology. 2023;23:213. doi: 10.1186/s12876-023-02764-w.

5. Baryshnikova N.V., Uspensky Y.P., Kalinina E.Y., Krasnov A.A. et al. Efficacy of alpha-glutamyl-tryptophan in inflammation resolution in patients with chronic atrophic gastritis associated with Helicobacter pylori infection.Russian J of Evidence-based Gastroenterology. 2022;11 (4):15-21. (in Russ.) doi: 10.17116/dokgastro2022110311.@@ Барышникова Н.В., Успенский Ю.П., Калинина Е.Ю., Краснов А.А. и соавт. Эффективность альфа-глутамил-триптофана в купировании воспаления у больных хроническим атрофическим гастритом, ассоциированным с Helicobacter pylori. Доказательная гастроэнтерология. 2022;11 (4):15-21. doi: 10.17116/dokgastro2022110311.

6. Uspensky Y.P., Baryshnikova N.V., Krasnov A.A., Petlenko S.V. et al. Effects of Regastim Gastro on the restoration of gastric acid secretion according to 24-hour pH monitoring in patients with chronic atrophic gastritis. Exper and clin gastroenterology. 2022;198 (2):40-47. (in Russ.) doi: 10.31146/1682-8658-ecg-198-2-40-47.@@ Успенский Ю.П., Барышникова Н.В., Краснов А.А., Петленко С.В. и соавт. Влияние Регастим Гастро на восстановление кислотопродукции в желудке по данным суточной рН-метрии у больных хроническим атрофическим гастритом. Экспериментальная и клиническая гастроэнтерология. 2022;198 (2):40-47. doi: 10.31146/1682-8658-ecg-198-2-40-47.

7. Uspensky Y.P., Baryshnikova N.V., Krasnov A.A., Petlenko S.V. et al. Current issues in gastric cancer prevention. Consilium medicum. 2022;24(5): 358-364. (in Russ.) doi: 10.26442/20751753.2022.5.201922.@@ Успенский Ю.П., Барышникова Н.В., Краснов А.А., Петленко С.В. и соавт. Актуальные вопросы профилактики рака желудка. Consilium medicum. 2022;24(5): 358-364. doi: 10.26442/20751753.2022.5.201922.

8. Gubin M.M., Vesely M.D. Cancer Immunoediting in the Era of Immuno-oncology. Clin Cancer Res. 2022;28(18):3917-3928. doi: 10.1158/1078-0432.CCR-21-1804.

9. Bai Y., Xu H., Guo M., Xia L. et al. Extensive infiltration of CD8+ T cells and M1 macrophages is beneficial for multiple cancer patients undergoing chemotherapy. Med Comm-Oncology. 2024; 3(3): e89. doi: 10.1002/mog2.89.

10. Clinical pharmacology of Thymogen / Eds. Smirnov V.S. - St. Petersburg: AISING, 2012. - 108 p. (in Russ.) Available at: https://cytomed.ru/wp-content/uploads/2023/12/klinicheskaya-farmakologiya-timogena.pdf (Accessed: 01.12.2025.)@@ Клиническая фармакология тимогена / Под ред. В.С. Смирнова. - СПб: АЙСИНГ, 2012. - 108 с. https://cytomed.ru/wp-content/uploads/2023/12/klinicheskaya-farmakologiya-timogena.pdf

11. Directive 2010/63/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes. Official Journal of the European Union. 2010;53: 33-79.

12. Wu Z., Zheng Y., Sheng J. et al. CD3+CD4-CD8- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer. Front. Immunol. 2022;13: 816005. doi: 10.3389/fimmu.2022.816005.

13. Zhang Z.X., Ma Y., Wang H. et al. Double-negative T cells, activated by xenoantigen, lyse autologous B and T cells using a perforin/granzyme-dependent, Fas-Fas ligand-independent pathway. J Immunol. 2006;177(10):6920-9. doi: 10.4049/jimmunol.177.10.6920.

14. Lasek W. Cancer immunoediting hypothesis: history, clinical implications and controversies. Cent Eur J Immunol. 2022;47(2):168-174. doi: 10.5114/ceji.2022.117376.

15. Gu K.J., Li G. An overview of cancer prevention: chemoprevention and immunoprevention. J Cancer Prev. 2020;25(3):127-135. doi: 10.15430/JCP.2020.25.3.127.

16. Rosca E.V., Koskimaki J.E., Rivera C.G. et al. Anti-angiogenic peptides for cancer therapeutics. Curr Pharm Biotechnol. 2011;12(8):1101-1116. doi: 10.2174/138920111796117300.

17. Smith D.L., Cai J., Zhu S.T. et al. Natural killer cell cytolytic activity is necessary for in vivo antitumor activity of the dipeptide L-glutamyl-L-tryptophan.Int J Cancer. 2003;106(4):528-533. doi: 10.1002/ijc.11253.

18. Tulpule A., Scadden D.T., Espina B.M. et al. Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposi’s sarcoma. J Clin Oncol. 2000;18(4):716-723. doi: 10.1200/JCO.2000.18.4.716.

19. Bespalov V.G. [Synthetic and nature antitumor agents in cancer prevention]. Diss… med science., St. Petersburg, 2004. 46 p. (in Russ.) Available at: https://www.dissercat.com/content/sinteticheskie-i-prirodnye-antikantserogennye-veshchestva-v-profilaktike-raka (Accessed: 01.12.2025.)@@ Беспалов В.Г. Синтетические и природные антиканцерогенные вещества в профилактике рака. Автореф. дисс., СПб., 2004; 46 с. https://www.dissercat.com/content/sinteticheskie-i-prirodnye-antikantserogennye-veshchestva-v-profilaktike-raka

20. Anisimov V.N., Khavinson V. Kh., Morozov V.G. Immunomodulatory synthetic dipeptide L-Glu-L-Trp slows down aging and inhibits spontaneous carcinogenesis in rats. Biogerontology. 2000;1:55-59. doi: 10.1023/a:1010042008969.

21. Deplanque G., Madhusudan S., Jones P.H. et al. Phase II trial of the antiangiogenic agent IM862 in metastatic renal cell carcinoma. British Journal of Cancer. 2004;91:1645-1650. doi: 10.1038/sj.bjc.6602126.

22. Ferrario A., Tiehl von K.F., Rucker N. et al. Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma. Cancer Res. 2000;60:4066-4069.

23. Khedr S., Ameln A.K.-von, Khedr M. et al. Characterization of tryptophan-containing dipeptides for anti-angiogenic effects. Acta Physiologica. 2021;231: e13556. doi: 10.1111/apha.13556.

24. Kudryavtseva T.A., Starikova E.A., Aktureeva N.A. et al. Influence of glutamyl-tryptophan on the expression of IL-8 and ICAM-1 by mononuclear leukocytes of human peripheral blood and Ea.hy 926 cell line.Russian J of Immunology. 2017;11(20),2:157-158. (in Russ.)@@ Кудрявцева Т.А., Старикова Э.А., Актуреева Н.А. и соавт. Влияние глутамил-триптофана на экспрессию IL-8 и ICAM-1 мононуклеарными лейкоцитами периферической крови человека и клетками линии Ea.hy 926. Российский иммунологический журнал. 2017;11(20),2:157-158.

25. Golovacheva E.G., Starikova E.A., Kudryavtseva T.A., Apryatina V.A. The effect of drug with α-glutamyl-tryptophan for cytokine secretion and level of surface molecule ICAM-1 in vitro. Cell and Tissue Biology. 2023;17(2):146-152. doi: 10.1134/S1990519X23020050.

26. Radisavljevic Z., Avraham H., Avraham S. Vascular endothelial growth factor up-regulates ICAM-1 expression via the phosphatidylinositol 3 OH-kinase/AKT/Nitric oxide pathway and modulates migration of brain microvascular endothelial cells. The journal of Biological Chemistry. 2000;275(27):20770-20774. doi: 10.1074/jbc.M002448200.

27. Noy A., Scadden D.T., Lee J. et al. Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi’s sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy: from the AIDS malignancy consortium and IM862 study team. J Clin Oncol. 2005;23(5):990-998. doi: 10.1200/JCO.2005.11.043.

28. Wang S., Wang J., Chen Z. et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precis Oncol. 2024;8(1):31. doi: 10.1038/s41698-024-00522-z.

29. Park J.A., Espinosa-Cotton M., Guo H.-F. et al. Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody. J Immunother Cancer. 2023;11(3): e006680. doi: 10.1136/jitc-2023-006680.

30. Gonçales M., Warwas K.M., Meyer M. et al. Reversal of endothelial cell anergy by T cell-engaging bispecific antibodies. Cancers (Basel). 2024;16(24):4251. doi: 10.3390/cancers16244251.


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For citations:


Savelyev S.A., Murazov Ya.G., Beltiukov P.P., Baryshnikova N.V., Petlenko S.V. Assesment of changes in the pattern of immune cell infi ltrate subpopulation in syngeneic MC38 colorectal cancer during course administration of glutamyltryptophan: an experimental study. Experimental and Clinical Gastroenterology. 2025;(12):163-176. https://doi.org/10.31146/1682-8658-ecg-244-12-163-176

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