CC BY
17South Russian Journal of Cancer
South Russian Journal of Cancer 2023. Vol. 4, No. 1. P. 34-42 https://doi.org/10.37748/2686-9039-2023-4-1-4 https://elibrary.ru/hchskm ORIGINAL ARTICLE
MAJOR AND MINOR POPULATIONS OF LYMPHOCYTES: LOCAL FEATURES IN DIFFERENT STAGES OF COLON CANCER
A. B. Sagakyants1, E. A. Dzhenkova1, E. A. Mirzoyan10, I. A. Novikova1, E. Yu. Zlatnik1, E. S. Bondarenko1, A. V. Shaposhnikov1, A. A. Maslov1, O. Yu. Kaymakchi2, Yu. V. Przhedetskiy1, A. N. Shevchenko1
BY 4.0
1. National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation
2. Rostov State Medical University, Rostov-on-Don, Russian Federation E [email protected]
ABSTRACT
Purpose of the study. Was to reveal characteristics of the immunocompetent cells in colon cancer (CC) according to the disease stage, and to identify prognostic factors of cancer development.
Materials and methods. The study included 50 patients with CC: stage I - 4 patients (8 %), II - 25 (50 %), III - 21 (42 %). All patients underwent standard surgical intervention at the initial stage, the obtained material was used for subsequent studies: a cell suspension was obtained from the tumor tissue, peritumoral zone (1-3 cm from the tumor), which was treated with an antibody panel (Becton Dickinson, USA) to identify the main subpopulations of leukocytes and lymphocytes. Results. The tumor tissues of patients with stages I + II showed a decrease in the relative number of DR DN, NKT and CD19+, compared to peritumoral tissues, by 33 %, 42 %, 31 % and 82 % respectively. Tumor tissues of stage III patients demonstrated elevated relative numbers of CD3+, CD4+, NK by 57 %, 34 %, 48 %, and decreased DR DN, NKT, CD19+ by 33 %, 74 %, 31 %, 59 %, compared to peritumoral tissues. DR DN, NKT and CD19+ in the tumor decreased by 78 %, 74 %, 39 %, 60 %, respectively, and the relative number of lymphocytes increased by 138 %, compared to the tissues of the resection line. A comparative analysis of local immunological parameters in the tumor tissues of patients with CC revealed that the relative numbers of lymphocytes and CD19+ were 58 % and 87 % higher, and DR and DN were 33 % and 27 % lower in tumor tissues of stage III patients, compared to tumor tissues of stage I + II patients.
Conclusion. Thus, the obtained features of the local population and subpopulation composition of immunocompetent cells in CC, depending on the stage of the tumor process, can be used to predict the clinical course of the disease.
Keywords:
oncology, colon cancer, local cellular immunity
For correspondence:
Ellada A. Mirzoyan - PhD student, National Medical Research Centre of Oncology, Rostov-on-Don, Russian Federation.
Address: 63 14 line str., Rostov-on-Don 344037, Russian Federation
E-mail: [email protected]
ORCID: https://orcid.org/0000-0002-0328-9714
SPIN: 2506-8605, AuthorlD: 1002948
ResearcherlD: AAZ-2780-2021
Scopus Author ID: 57221118516
The work followed the ethical principles set forth by the Helsinki Declaration of the World Medical Association (World Medical Association Declaration of Helsinki, 1964, ed. 2013). The study was approved by the Ethics Committee of the National Medical Research Centre for Oncology (Protocol No. 32 of 10/08/2020). Informed consent was obtained from all participants of the study.
Funding: the work was performed as part of the state assignment on the "Development of prognostic and predictive algorithms based on the identification of new immunological and molecular genetic characteristics of malignant tumors and their microenvironment" topic, regist. No. 121031100251-9.
Conflict of interest: authors report no conflict of interest. For citation:
Sagakyants A. B., Dzhenkova E. A., Mirzoyan E. A., Novikova I. A., Zlatnik E. Yu., Bondarenko E. S., Shaposhnikov A. V., Maslov A. A., Kaymakchi O. Yu., Przhedetskiy Yu. V., Shevchenko A. N. Major and minor populations of lymphocytes: local features in different stages of colon cancer. South Russian Journal of Cancer. 2023; 4(1):34-42. https://doi.org/10.37748/2686-9039-2023-4-1-4, https://elibrary.ru/hchskm
The article was submitted 11.10.2022; approved after reviewing 10.01.2023; accepted for publication 06.03.2023.
© Sagakyants A. B., Dzhenkova E. A., Mirzoyan E. A., Novikova I. A., Zlatnik E. Yu., Bondarenko E. S., Shaposhnikov A. V., Maslov A. A., Kaymakchi O. Yu., Przhedetskiy Yu. V., Shevchenko A. N., 2023
Южно-Российский онкологический журнал 2023. Т. 4, № 1. С. 34-42
https://doi.org/10.37748/2686-9039-2023-4-1-4
https://elibrary.ru/hchskm
3.1.6. Онкология, лучевая терапия
ОРИГИНАЛЬНАЯ СТАТЬЯ
ОСНОВНЫЕ И МИНОРНЫЕ ПОПУЛЯЦИИ ЛИМФОЦИТОВ: ЛОКАЛЬНЫЕ ОСОБЕННОСТИ ПРИ РАЗЛИЧНЫХ СТАДИЯХ РАКА ОБОДОЧНОЙ КИШКИ
А. Б. Сагакянц1, Е. А. Дженкова1, Э. А. Мирзоян1^, И. А. Новикова1, Е. Ю. Златник1, Е. С. Бондаренко1, А. В. Шапошников1, А. А. Маслов1, О. Ю. Каймакчи2, Ю. В. Пржедецкий1, А. Н. Шевченко1
1. НМИЦ онкологии, г. Ростов-на-Дону, Российская Федерация
2. РостГМУ г. Ростов-на-Дону, Российская Федерация И [email protected]
РЕЗЮМЕ
Цель исследования. Выявить особенности состава иммунокомпетентных клеток при раке ободочной кишки (РОК) в зависимости от стадии процесса и выделить прогностические факторы течения заболевания. Материалы и методы. В исследование включено 50 пациентов РОК: I стадия - 4 пациента (8 %), II - 25 (50 %), III - 21 (42 %). Всем больным на начальном этапе было выполнено стандартное оперативное вмешательство. Полученный материал был использован для последующих исследований: из ткани опухоли, перитуморальной зоны (1-3 см от опухоли) была получена клеточная суспензия, которую обрабатывали при помощи панели антител (Becton Dickinson, USA) для выявления основных субпопуляций лейкоцитов и лимфоцитов.
Результаты. В тканях опухолей группы пациентов I + II стадии отмечено уменьшение относительного количества ДП, ДН, NKT и CD19+ по сравнению с перитуморальной зоной на 33 %, 42 %, 31 % и 82 % соответственно. В тканях опухоли пациентов с III стадией выявлено повышение относительного количества CD3+, CD4+, NK на 57 %, 34 %, 48 % и снижение ДП, ДН, NKT, CD19+ на 33 %, 74 %, 31 %, 59 % по сравнению с тканью перитуморальной зоны. В опухоли выявлено уменьшение ДП, ДН, NKT, CD19+ на 78 %, 74 %, 39 %, 60 %, а также увеличение относительного количества лимфоцитов по сравнению с линией резекции на 138 % соответственно. При проведении сравнительного анализа локальных иммунологических показателей в тканях опухолей больных РОК выявлено, что в тканях опухолей группы пациентов III стадии отмечено увеличение относительного количества лимфоцитов и CD19+ на 58 % и 87 % и снижение ДП и ДН на 33 % и 27 % по сравнению с тканями опухолей группы I + II стадии.
Заключение. Таким образом, полученные особенности локального популяционного и субпопуляционного состава иммунокомпетентных клеток при РОК в зависимости от стадии опухолевого процесса могут быть использованы при прогнозировании клинического течения заболевания.
Ключевые слова:
онкология, рак ободочной кишки, локальный клеточный иммунитет
Для корреспонденции:
Мирзоян Эллада Арменовна - аспирант, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация. Адрес: 344037, Российская Федерация, г. Ростов-на-Дону, ул. 14-я линия, д. 63 E-mail: [email protected]
ORCID: https://orcid.org/0000-0002-0328-9714, SPIN: 2506-8605, AuthorlD: 1002948 ResearcherlD: AAZ-2780-2021, Scopus Author ID: 57221118516
В работе соблюдались этические принципы, предъявляемые Хельсинкской декларацией Всемирной медицинской ассоциации (World Médical Association Déclaration of Helsinki, 1964, ред. 2013). Исследование одобрено этическим комитетом ФГБУ «НМИЦ онкологии» Минздрава России (протокол № 32 от 08.10.2020 г.). Информированное согласие получено от всех участников исследования.
Финансирование: работа выполнена в рамках выполнения государственного задания по теме «Разработка прогностических и предиктивных алгоритмов на основе выявления новых иммунологических и молекулярно-генетических характеристик злокачественных опухолей и их микроокружения», рег. № 121031100251-9. Конфликт интересов: авторы заявляют об отсутствии конфликта интересов.
Для цитирования:
Сагакянц А. Б., Дженкова Е. А., Мирзоян Э. А., Новикова И. А., Златник Е. Ю., Бондаренко Е. С., Шапошников А. В., Маслов А. А., Каймакчи О. Ю., Пржедецкий Ю. В., Шевченко А. Н. Основные и минорные популяции лимфоцитов: локальные особенности при различных стадиях рака ободочной кишки. Южно-Российский онкологический журнал. 2023; 4(1):34-42. https://doi.org/10.37748/2686-9039-2023-4-1-4, https://elibrary.ru/hchskm
Статья поступила в редакцию 11.10.2022; одобрена после рецензирования 10.01.2023; принята к публикации 06.03.2023.
RELEVANCE
Colorectal cancer (CRC) occupies one of the first places in the structure of morbidity from cancer in the Russian Federation [1; 2]. About 60 % of cases of CRC occur in colon cancer (CC), which occupies the 4th place in the structure of female cancer incidence, the 5th place - male cancer incidence [3].
To date, there are a large number of modern methods of diagnosing the oncoprocess. However, despite this, the level of neglect of colon tumors remains quite high. As a rule, at the time of treatment of patients, the cancer process has advanced stages [4; 5].
More and more research in oncology is associated with the study of the role of the links of the immune system in the occurrence, course, and progression of the cancer process. Its dual role has been proven: on the one hand, the presence of antitumor effects, on the other - tumor-activating. This fact determines the relevance of studying the role of individual components of both innate and adaptive immunity in colocancerogenesis.
The immune system of the gastrointestinal tract plays an important role in protecting the body from the action of infectious agents and toxins, their in-activation and elimination is carried out. It has been proven that both local and systemic inflammatory reactions play an important role in the progression of the tumor process, thereby affecting the outcome of the disease [6; 7]. Colorectal tumors are infiltrated by immune and inflammatory cells, the most significant of which are T-lymphocytes. It is also known that the tissue of tumors of the colon and rectum contains a small number of T-lymphocytes with CD4+ and CD8+ receptors [8].
Fig. 1. Distribution of patients according to their disease stage.
Infiltration by macrophages of the tumor and perifocal zone is used as a prognostic factor: low infiltration density is associated with high invasive properties of tumors [9; 10]. There are a number of works in the literature devoted to the study of tumor-infiltrating immunocompetent cells and the assessment of their prognostic significance in CRC, which are very contradictory [11 -13]. There is no doubt about the high importance of studying the role of tumor infiltration of lymphocytes, which determine the biological properties of the tumor and the features of the clinical course of the disease. At the same time, there is a small amount of information reflecting the features of lymphocytic infiltration in the tumor tissue, perifocal zone, resection line, depending on the stage of the disease, which determines the purpose of the study.
Purpose of the study was to identify the features of the population and subpopulation composition of immunocompetent cells locally in colon cancer, depending on the stage of the process and to identify prognostic factors of the course of the disease.
MATERIALS AND METHODS
The study included 50 patients with CC who were treated at the National Medical Research Centre for Oncology: 26 of them were women (52 %), whose average age was 67 ± 0.4 years and 24 men (48 %), the average age was 66 ± 0.3 years.
According to the results of postoperative histological analysis, the following distribution was revealed by stages of CC: I - 4 patients (8 %), II - 25 (50 %), III - 21 (42 %), subsequently patients of groups I and II were combined (Fig. 1).
The spread of the tumor within the intestinal wall (T1 -3) was noted in 38 (76 %) patients, and a tumor that sprouted into other organs and/or visceral peritoneum T4 - in 12 (24 %). Regional lymph nodes (l.n.) (N+) were affected in 27 patients (54 %). At the 1st stage of treatment, all patients underwent surgical intervention with the collection of material for subsequent studies. A cell suspension was obtained from tumor tissues, the peritumoral zone, and the resection line, processed using an antibody panel (Becton Dickinson, USA) in order to identify the main populations and subpopulations of leukocytes and lymphocytes using a BD FACSCanto flow cytometer (Becton Dickinson, USA). The results were expressed in the relative number of the main populations and
subpopulations of lymphocytes: CD45+ - total number of lymphocytes (Lymph), CD3+ - T-lymphocytes, CD3+CD4+ - T-lymphocytes helper, CD3+CD8+ -cytotoxic T-lymphocytes, CD3+CD4+CD8+ - double positive lymphocytes (DP), CD3+CD4-CD8- - double negative lymphocytes (DN), CD3-CD56+CD16+ - NK lymphocytes, CD3+CD56+CD16+ - NKT lymphocytes, CD19+ - B lymphocytes relative to the total number of lymphocytes.
Statistical processing of the obtained results was carried out using the STATISTICA 13.3 package (StatSoft Inc., USA), which involved calculating the main statistical characteristics of the samples, determining the nature of the distribution of the determined indicators using the Shapiro-Wilk criterion. Due to the fact that the obtained results did not obey the law of normal distribution, the reliability of the differences between the samples was evaluated using the nonparametric Mann-Whitney criterion. The results were considered statistically significant at p < 0.05.
RESEARCH RESULTS AND DISCUSSION
We conducted a comparative analysis of the relative number of the main populations and subpopulations of lymphocytes, depending on the stage, the depth of the lesion of the intestinal wall tumor (T), the presence or absence of lesion of regional lymph nodes (N).
When analyzing the data, depending on the stage of the tumor process, it was revealed that in the tumor tissues of the group of patients of stage I-II, there was a decrease in the relative number of DR and DN cells, NKT and CD19+ lymphocytes compared with similar indicators in the peritumoral zone by 33 %, 42 %, 31 % and 82 %, respectively (p < 0.05). Compared with conditionally healthy tissue, tumor fragments showed an increase in the relative number of T-lymphocytes, CD3+ and NK cells by 41 %, 35 %, 50 %, while the content of DR-, DN-, NKT-, CD19+ lymphocytes was reduced by 33 %, 42 %, 31 %, 82 % (p < 0.05).
CD3+ CD4+ CD8+ CD19+ LVMPH DP DN NK NKT
Fig. 2. Subpopulation composition in the tissues of patients with stage I - II colon cancer.
Note: д - statistically significant differences from the indicators of the resection line (conditionally healthy tissue); * - statistically significant differences from the indicators of the peritumoral zone.
CD3+ CD4+ CD8+ DN CD19+ LYMPH DP
Fig. 3. The subpopulation composition in the tissues of the group of patients with stage III colon cancer.
Note: д - statistically significant differences from the indicators of the resection line (conditionally healthy tissue); * - statistically significant differences from the indicators of the peritumoral zone.
In the peritumoral zone, a low content of CD19+ (by 52 %) was noted, as well as an increased content of lymphocytes, CD8+, DP, NK, NKT on 62 %, 25 %, 27 %, 36 % and 69 %, respectively, compared with the indicators in the resection line (p < 0.05)
(fig. 2).
Analysis of the results of the study of tissues of patients with stage III CC showed that in the tumor tissue there is an increase in the relative number of CD3+, CD4+, NK lymphocytes by 57 %, 34 %, 48 % and a decrease in DP, DN, NKT, CD19+ cells by 33 %, 74 %, 31 %, 59 % by compared with the tissue of the peritumoral zone (p < 0.05). In the tumor, there is a decrease in DP, DN, NKT, CD19+ by 78 %, 74 %, 39 %, 60 %, against this background, an increase in the relative number of lymphocytes compared to the resection line was revealed by 138 %, respectively (p < 0.05) (Fig. 3).
A comparative analysis of local immunological parameters in the tumor tissues of CC patients revealed that in the tumor tissues of the group of stage III
patients there was an increase in the relative number of lymphocytes and CD19+ cells by 58 % and 87 % and a decrease in DP and DN of lymphocytes by 33 % and 27 % compared with the tissues of tumors of stage I and II (p < 0.05) (fig. 4).
Based on the data obtained, it was revealed that the tumor is characterized by the accumulation of T-lymphocytes, in particular, T-helper-inductor and B-cells (CD19+), which is especially pronounced in stage III of the disease in patients with CC and a low content of DP and DN lymphocytes, as well as NKT cells.
The existing data in the literature indicate that the tissue of tumors of the colon and rectum is infiltrated by a small number of T-lymphocytes. In 1987, J. R. Jass et al. It has been shown that pronounced lymphocytic infiltration of the perifocal zone is a prognostic factor for longer overall survival of CRC patients [11-13]. It has been proven that the pronounced accumulation of CD8+ T cells in tumor tissue correlates with longer survival of patients [14; 15].
Fig. 5. The subpopulation composition in the tumor tissues of a group of colon cancer patients, depending on the criterion T. Note: * - statistically significant differences (p < 0.05).
Analysis of the subpopulation composition of lymphocytes in tumor tissue, depending on the criterion of the level of invasion of the intestinal wall tumor (T), showed that in the tumor tissues of the T4 patient group, an increase in the relative number of DP cells and CD19+ lymphocytes was noted compared to the tissues of the T1 -3 group by 56 % and 186 %, respectively (p < 0.05), and also, a decrease in the relative number of NKT lymphocytes by 41 % (p < 0.05) (fig. 5).
When comparing the results obtained, depending on the lymph node lesion, it was noted that in the tumor tissues of the group of patients with node lesion (N+), an increase in the relative number of lymphocytes and CD19+ was noted by 96 % and 97 %, as well as a decrease in the relative number of NKT lymphocytes by 32 % compared with the tumor tissues of the group of patients N0 (p < 0.05) (Fig. 6).
Our results somewhat contradict the data of Tachi-bana T. et al., according to which tumor infiltration by NKT cells positively correlated with a smaller number of lymph node metastases [16].
By a group of authors A. C. Diederichsen et al. It has been demonstrated that a low CD4+/CD8+ ratio, i.e. the prevalence of cytotoxic T-lymphocytes in the tumor against the background of a decrease in T-cells with helper-inductor function, is a prognostic factor for long-term survival of CRC patients [17]. The data obtained in our study, indicating certain features of the tissue composition of immunocompetent cells in the tumor and its microenvironment, in some cases agree with the data of other authors and may, in our opinion, be the basis for the development of criteria for the prognosis of the development of CRC metastases [18].
DN lymphocytes - Pinocchio cells (Pinocchio cells) are intermediate elements of differentiating T-lymphocytes. This type of cells resembles cells of innate immunity in functional activity, they form early barrier formations aimed at maintaining immune homeostasis [19].
When studying the features of the immunological organization of soft tissue sarcomas, it was shown that in the tissue of recurrent sarcomas there is a high level of DN T-lymphocytes, which belong to a subpopulation of T cells with TCRyA and may have the properties of T-regs [20]. An increase in their level in the blood in some malignant tumors presupposes some negative changes in the immune status [21].
However, there is also an opposite opinion, according to which both DN and DP lymphocytes, being cells of innate immunity, have the opposite effect. In our study, the opposite trend was found - in the case of disease progression, its later stages or the presence of metastases, it was accompanied by an increase in the content of these cells, which, however, does not allow us to draw a final conclusion about the functional significance of this fact.
Currently, there is no clear opinion about the role of B-lymphocytes in the development of tumors and sensitivity to therapy. It has been shown that the number of circulating antibodies increases in the blood of cancer patients, and in the tumor tissue of tumor-infiltrating B-lymphocytes, which perform a protective function [22]. According to another opinion, B cells increase the aggressiveness of the tumor, thereby worsening the prognosis [23]. Under certain conditions, B cells can perform the function of antigen-presenting cells: express stimulating CD80, CD86 and ICOS molecules and activate CD4+, CD8+ T cells [24].
Fig. 6. The subpopulation composition in the tumor tissues of the CC patient group, depending on criterion N. Note: * - statistically significant differences (p < 0.05).
However, activated B-lymphocytes and plasmocytes synthesize antibodies that block the antigens of tumor cells, disrupting their recognition [25]. It has been shown that one of the varieties of B-lympho-cytes are cells with high regulatory potential, which is expressed in the secretion of IL-10, IL-35, IL-6, transforming growth factor-p (TGF-p), which causes immunosuppression of antitumor immunity [26] Despite certain differences in the results of studying the immunological microenvironment of various malignant tumors obtained by various research groups, understanding the mechanisms involved in the interaction between tumor cells and the microenvironment opens up a great prospect for changing the treatment strategy that will help fight tumors more effectively [27].
CONCLUSION
1. The tumor tissue in CC is characterized by the accumulation of T-helper-inductor lymphocytes and
B cells (CD19+) and depletion of DP and DN lymphocytes, as well as a decrease in the number of NKT cells, which is more pronounced in stage III of the disease in patients with CC.
2. At the III stage of the disease, in CC, there is a decrease in the activity of local innate immunity, which is manifested in a decrease in the content of NKT cells in the primary tumor, as well as the tension of the humoral link of immunity, due to the high content of tumor CD19+ lymphocytes, the same trend is observed with the defeat of regional lymph nodes (N+).
3. It is possible that an increased number of CD19+ cells is a factor predisposing to the occurrence of lymphogenic metastasis, and is also associated with a more advanced stage of CC.
Thus, the data obtained on the features of the local population and subpopulation composition of immunocompetent cells in colon cancer, depending on the stage, T and N, can be used in the prognosis of the clinical course of the disease.
References
1. Kit OI. The problem of colorectal cancer at the beginning of the XXI century: achievements and prospects. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2013;23(3):65-71. (In Russ.).
2. Maratkyzy M, Kabildina NA, Beisenayeva AR, Sariybayeva VO. Epidemiological aspects of colorectal cancer. Medicine and Ecology. 2020;(2(95)):15-20. (In Russ.).
3. Malignant neoplasms in Russia in 2020 (morbidity and mortality). Ed. by A. D. Kaprin, V. V. Starinsky, A. O. Shakhzadova. Moscow: P. A. Herzen MNIOI - Branch of the National Medical Research Radiological Center, 2021, 252 p. (In Russ.).
4. Dzhenkova EA, Mirzoyan EA, Sagakyants AB, Bondarenko ES, Zlatnik EYu, Shaposhni-kov AV, et al. Evaluation of Toll-like receptors expression in terms of colon cancer. Research and Practical Medicine Journal. 2022;9(4):63-71. (In Russ.). https://doi.org/10.17709/2410-1893-2022-9-4-6, EDN: FMSXBE
5. Osombaev MSh, Dzhekshenov MD, Satybaldiev OA, Abdrasulov KD, Makimbetov EK, Kuzikeev MA. Epidemiology of Colorectal Cancer. Scientific Review. Medical Sciences. 2021;(1):37-42. (In Russ.). EDN: LYEMDE
6. Kit OI, Dzhenkova EA, Mirzoyan EA, Sagakyants AB, Bondarenko ES, Zlatnik EYu, et al. Characteristics of local cellular immunity in colon cancer depending on tumor location. Modern Prob-lems of Science and Education. 2022;(3):86. (In Russ.). https://doi.org/10.17513/spno.31695, EDN: BEXJYR
7. Kit OI, Zlatnik EYu, Nikipelova EA, Gevorkyan YuA, Averkin MA, Novikova IA, et al. Peculiarities of general and local immunity at solitary and synchronous primary-multiple colon cancer. Modern Problems of Science and Education. 2012;(5):38. (In Russ.). EDN: PKWSEZ
8. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011 Mar 25;331(6024):1565-1570. https://doi.org/10.1126/science.1203486
9. Gratz IK, Rosenblum MD, Abbas AK. The life of regulatory T cells. Ann N Y Acad Sci. 2013 Apr;1283:8-12. https://doi.org/10.1111/nyas.12011
10. Väyrynen JP, Tuomisto A, Klintrup K, Mäkelä J, Karttunen TJ, Mäkinen MJ. Detailed analy-sis of inflammatory cell infiltration in colorectal cancer. Br J Cancer. 2013 Oct 1;109(7):1839-1847. https://doi.org/10.1038/bjc.2013.508
11. Kit OI, Frantsiyants EM, Nikipelova EA, Komarova EF, Kozlova LS, Tavaryan IS et al. Changes in markers of proliferation, neoangiogenesis and plasminogen activation system in rectal cancer tissue. Experimental and Clinical Gastroenterology. 2015;(2(114)):40-45. (In Russ.). EDN: THKCLP
12. Pages F, Galon J, Fridman WH. The essential role of the in situ immune reaction in human colorectal cancer. J Leukoc Biol. 2008 Oct;84(4):981 -987. https://doi.org/10.1189/jlb.1107773
13. Grizzi F, Bianchi P, Malesci A, Laghi L. Prognostic value of innate and adaptive immunity in colorectal cancer. World J Gastroenterol. 2013 Jan 14;19(2):174-184. https://doi.org/10.3748/wjg.v19.i2.174
14. Mei Z, Liu Y, Liu C, Cui A, Liang Z, Wang G, et al. Tumour-infiltrating inflammation and prognosis in colorectal cancer: systematic review and meta-analysis. Br J Cancer. 2014 Mar 18;110(6):1595-1605. https://doi.org/10.1038/bjc.2014.46
15. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, et al. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer. 2004 Nov 1;91(9):1711-1717. https://doi.org/10.1038/sj.bjc.6602201
16. Tachibana T, Onodera H, Tsuruyama T, Mori A, Nagayama S, Hiai H, et al. Increased intra-tumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin Cancer Res. 2005 Oct 15;11(20):7322-7327. https://doi.org/10.1158/1078-0432.CCR-05-0877
17. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010 Dec;222(4):350-366. https://doi.org/10.1002/path.2774
18. Nikipelova EA, Kit OI, Shaposhnikov AV, Zlatnik EYu, Novikova IA, Vladimirova LYu, et al. Immunologic criteria for the development of distant metastases from colon cancer. News of High-er Educational Institutions. The North Caucasus Region. Series: Natural Sciences. 2017;(3-2(195-2)):96-101. (In Russ.). https://doi.org/10.23683/0321-3005-2017-3-2-96-101, EDN: ZQTDAB
19. Khaitov RM, Kadagidze ZG. Immunity and cancer. Moscow: GEOTAR-media, 2018, 121 p.
20. Kawai K, Uchiyama M, Hester J, Wood K, Issa F. Regulatory T cells for tolerance. Hum Immunol. 2018 May;79(5):294-303. https://doi.org/10.1016/j.humimm.2017.12.013
21. Zlatnik EYu, Novikova IA, Nepomnyashchaya EM, Selyutina ON, Ausheva TV, Aliev TA et al. Possibility of predicting the efficiency of soft tissue sarcoma treatment on the basis of features of their immunological microenvironment. Kazan Medical Journal. 2018;99(1):167-173. (In Russ.). https://doi.org/10.17816/KMJ2018-167, EDN: YMRWJY
22. Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin к C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012 May 1;18(9):2695-2703. https://doi.org/10.1158/1078-0432.CCR-11 -2210
23. Zhou X, Su YX, Lao XM, Liang YJ, Liao GQ. CD19(+)IL-10(+) regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4(+) T cells to CD4(+)Foxp3(+) regulatory T cells. Oral Oncol. 2016 Feb;53:27-35. https://doi.org/10.1016/j.oraloncology.2015.11.003
24. Berntsson J, Nodin B, Eberhard J, Micke P, Jirstrom K. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J Cancer. 2016 Sep 1;139(5):1129-1139. https://doi.org/10.1002/ijc.30138
25. Fu SL, Pierre J, Smith-Norowitz TA, Hagler M, Bowne W, Pincus MR, et al. Immunoglobu-lin E antibodies from pancreatic cancer patients mediate antibody-dependent cell-mediated cytotoxici-ty against pancreatic cancer cells. Clin Exp Immunol. 2008 Sep;153(3):401-409. https://doi.org/10.1111/j.1365-2249.2008.03726.x
26. Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C, Barth TFE, et al. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res. 2013 Apr 15;73(8):2468-2479.
https://doi.org/10.1158/0008-5472.CAN-12-3450
27. Zibirov RF, Mozerov SA. Characterization of the tumor cell microenvironment. Oncology. P. A. Herzen Journal. 2018;7(2):67-72. https://doi.org/10.17116/onkolog20187267-72
Information about authors:
Aleksandr B. Sagakyants - Cand. Sci. (Biol.), associate professor, head of the laboratory of tumor immunophenotyping, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0003-0874-5261, SPIN: 7272-1408, AuthorlD: 426904, ResearcherlD: M-8378-2019, Scopus Author ID: 24329773900
Elena A. Dzhenkova - Dr. Sci. (Biol.), academic secretary, National Medical Research Centre, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-3561-098X, SPIN: 6206-6222, AuthorID: 697354, ResearcherID: K-9622-2014, Scopus Author ID: 6507889745
Ellada A. Mirzoyana - PhD student, National Medical Research Centre of Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-0328-9714, SPIN: 2506-8605, AuthorlD: 1002948, ResearcherlD: AAZ-2780-2021, Scopus Author ID: 57221118516 Inna A. Novikova - Cand. Sci. (Med.), deputy director for science, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-6496-9641, SPIN: 4810-2424, AuthorID: 726229, Researcher ID: E-7710-2018, Scopus Author ID: 7005153343 Elena Yu. Zlatnik - Dr. Sci. (Med.), professor, chief researcher of the laboratory of tumor immunophenotyping, National Medical Research Centre of Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-1410-122X, SPIN: 4137-7410, AuthorID: 327457, Scopus Author ID: 6603160432
Elena S. Bondarenko - junior research fellow at the laboratory of tumor immunophenotyping, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-8522-1026, SPIN: 3117-4040, AuthorID: 865798, Scopus Author ID: 57200132337 Alexander V. Shaposhnikov - Dr. Sci. (Med.), professor, chief researcher of the thoracoabdominal department, National Medical Research Centre of Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0001-6881-2281, SPIN: 8756-9438, AuthorID: 712823 Andrey A. Maslov - Dr. Sci. (Med.), professor, chief physician, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0001-7328-8074, SPIN: 5963-5915, AuthorID: 817983
Oleg Yu. Kaymakchi - Dr. Sci. (Med.), associate professor of oncology, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. AuthorID: 335064
Yuriy V. Przhedetskiy - Dr. Sci. (Med.), professor, head of the department of reconstructive plastic surgery and oncology, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0003-3976-0210, SPIN: 3888-6265, AuthorID: 702006, ResearcherID: ATT-7598-2020, Scopus Author ID: 57188731912
Alexey N. Shevchenko - Dr. Sci. (Med.), professor, head of the oncourology department, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation. ORCID: https://orcid.org/0000-0002-9468-134X, SPIN: 2748-2638, AuthorID: 735424, ResearcherID: Y-5387-2018, Scopus Author ID: 57192283096
Contribution of the authors:
Sagakyants A. B., Dzhenkova E. A., Novikova I. A. - scientific editing; Mirzoyan E. A. - text writing, data processing;
Zlatnik E. Yu., Bondarenko E. S., Shaposhnikov A. V., Maslov A. A., Kaymakchi O. Yu., Przhedetskiy Yu. V., Shevchenko A. N. - data collection, analysis, technical editing, bibliography design.
