Characteristics of local and system immunity, and features of cancer stem cells in patients with different stage, dynamics and prognosis of colorectal carcinoma

Clinical prognosis in malignant tumors` is among the most challenging problems of contemporary medicine. It is thought to depend on both biologic properties of tumor cells and patients` immune status. The features of tumor cells and immune reactions are closely interrelated and mutually conditioned. Therefore, possible application of their characteristics as prognostic markers is of great fundamental and clinical importance. The aim of our study is to find out the most significant immune factors for prognosis of colorectal cancer (CRC) based on estimation of local and system immune factors, and some characteristics of tumor cells in the patients at various stages of the disease and different clinical course. Cellular factors of immunity and cytokines were studied in blood and tumor tissue of 299 patients with colorectal cancer (stages I-IV). Malignant cells expressing stem cell markers CSC), MHC and PDL-1 molecules were also counted in the tumor tissue. Blood samples were drawn prior to operation, and tissue samples were taken during surgery being the 1st line of treatment. Flow cytometry techniques (FCM), immunohistochemistry (IHC), and ELISA approach were employed. We have compared data on the patients at different CRC stages (with or without local and distant metastases), as well as cases with different course of the disease (evolving distant metastases and fatal outcome during period of observation). Our results demonstrated increased amounts of NK-cells and IL-6 concentration, along with decreased percentage of blood CD4+ cells in the patients with local metastases, as well as higher CSC numbers in malignant tissue. The initially generalized CRC cases with distant metastases were characterized by high levels of blood IL-6, monocytes and granulocytes responding to fMLF, while in tumor tissue elevated amounts of NKT, CSC and decreased expression of MHC and PDL-1 were observed on tumor cells, like as lower PD-1/ PDL-1 expression on tumor-infiltrating lymhocytes. Unfavorable CRC dynamics, i.e., metastasizing during the observation period was preceded by increased levels of IL-10 in blood, NK cells with poor cytotoxicity, monocytes and granulocytes responding to fMLF. In tumor tissue, overexpression of CSC markers and hypo-expression of MHC on tumor cells were noted. Fatal outcome was preceded by elevation of blood IL-6levels, tissue levels of NKТ and CSC percentages, along with decreased NK cells subset (CD16dimCD56bright) in blood, and decline of MHC-expressing cells in the tumor. Thus, high blood levels of IL-6 and IL-10, fMLF-responding monocytes and granulocytes, as well as elevated amounts of NKT and CSC, hypo-expression of MHC in tumor tissue could be considered prognostic markers of unfavorable course in CRC patients. Decrease of PD-1/PDL-1 expression on tumor cells and lymphocytes from its microenvironment in advanced CRC is of special attention, because checkpoint inhibitors are prescribed in such cases

Expression level of androgen receptors in tumor tissue and its prognostic significance in primary operable luminal breast cancer without overexpression of Her2/neu in postmenopausal women

Aim. To evaluate the expression level and prognostic significance of androgen in primary operable luminal breast cancer without overexpression of Her2/neu in postmenopausal women. Methods. We analyzed treatment outcomes of 60 cases of primary operable (T1-2N0M0) luminal breast cancer without overexpression of Her2/neu in postmenopausal women. The follow-up period was 5 years. All cases were divided by immunohistochemical method into luminal A (20 females) and luminal B (40 patients) subtypes. Along with the standard panel of immunohistochemical markers, expression of nuclear androgen receptors was measured in tumor tissues of all patients. Depending on the expression levels, patients with luminal A and B subtypes were divided into three groups: (1) with high, (2) moderate and (3) low or negative expression. Results. Mean levels of androgen receptor expression in the nuclei of tumor cells in patients with luminal A subtype (57.3±5.9%) were higher than those of luminal B subtype (21.4±4.04%) by 62.7% (Mann-Whitney test, р=0.0026). In patients with luminal A subtype, the maximal accumulation of androgen receptors in the nuclei of tumor cells was 2.7 times higher (р=0.0023) than in patients with luminal B subtype. All cases diagnosed with the disease progression were characterized by low or negative level of nuclear androgen receptor expression. Conclusion. Negative and low levels of androgen receptor expression in tumor tissues of postmenopausal patients with luminal primary operable breast cancer without overexpression of Her2/neu might be an independent factor associated with poor prognosis

Achievements and prospects of cellular technologies based on the activated lymphocytes in the treatment of malignant tumors

This article reviews the immune system and its role in the relationship between the tumor and the body of a patient with tumor diseases. It is about controlling homeostasis by recognizing and eliminating genetically alien substances (antigens). Antitumor treatment is now not only considered as an “instrument” for eliminating and destroying tumor cells, but also its ability to change/restore impaired functions of the immune system attracts attention. The used antitumor treatment is widely known to be immunosuppressive, stress and radiation effects also cause and/or enhance immunosuppression. In this work, the authors provide literature data demonstrating current status and problems of cellular immunotherapy of malignant tumors with the use of activated lymphocytes, and the role of antigen-specific T-lymphocytes as one of its most important agents is reviewed. Currently, among the immunotherapeutic methods, a special place is occupied by approaches involving the use of autologous or allogenic ex vivo stimulated immunocompetent cells (adoptive immunotherapy). The importance of complex influence on various links (T-, B-, NK-cell) and stages (presentation, recognition, proliferation, differentiation, migration, activation, effector functions) of the immune response is considered. The emergence of targeted drugs based on antibodies, as well as vaccines, especially dendritic cells, has provoked the emergence of a new wave of interest in the formation of specific antitumoral immune response mediated by T lymphocytes, so the introduction of the latter can be classified as a kind of targeted therapy. The value of antigen-specific T-lymphocytes in the formation of antitumor immunity is shown, which emphasizes the importance not only of CD8+, but also of CD4+ T-lymphocytes. In addition, there are suggestions of the possible significance of both T- and B-cells for developing a strategy of cellular immunotherapy. The literature data suggest that not only cytotoxic lymphocytes, but also T-helpers and even B-lymphocytes can be effective as antigen-specific lymphocytes as a component of antitumor treatment. The authors consider the possibility of obtaining antigen-specific T cells, as well as their further storage. The possibility of elimination or selective inhibition of regulatory T-cells during adoptive immunotherapy aimed at removing the suppressor effect on cytotoxic lymphocytes is studied. Various strategies for the use of cell therapy are also discussed

Comparative analysis of some immunological parameters depending on the tumor location on the right and left sides of colon

Background: Colorectal cancer is now an urgent problem in oncology. Recently, specialists have been interested in a comparative analysis of differences in the clinical course of malignant tumors in the proximal and distal colon. The sections differ not only in their embryogenesis and sources of blood supply, but also in the clinical course and population and epidemiological characteristics. The issue of distinctive immunological characteristics of tumors of the colon depending on the location remains open.Objective: A comparative analysis of local subpopulations of immunocompetent cells and an assessment of number of cells with the CD45+/- phenotype expressing toll-like receptors (TLRs) depending on the tumor location on the right or left sides of the colon.Material and methods: The study included 50 patients with verified colon cancer. The majority of patients were females – 26 (52%), aged 67 ± 0.4 years, and 50% of patients with stage II disease. Depending on the tumor location (the right or left sides of the colon), the patients were divided into 2 groups of 25 people each. All patients underwent standard surgery at the initial stage. The obtained material was used for subsequent studies: a cell suspension was obtained from a tumor tissue fragment, the perifocal zone (1–3 cm from the tumor) which was processed using an antibody panel (Becton Dickinson, USA) to identify the main subpopulations of leukocytes and lymphocytes. Expression of TLRs (2, 3, 4, 8, 9) on CD45+, CD45- cell populations was also determined using the BD FACSCanto flow cytometer (Becton Dickinson, USA). Statistical processing of the results was performed using the STATISTICA 13.3 package (StatSoft Inc., USA).Results: A comparative analysis of immunological parameters, depending on the tumor location on the right or left sides of the colon, showed:Tissues of the right-sided tumors had a higher T-lymphocytic infiltration, compared to the left-sided tumors, while the latter showed a higher B-lymphocytic infiltration (p = 0.025).Peritumoral zone tissues of left-sided tumors demonstrated a decrease of lymphocytes levels (p = 0.027), NKT – (p = 0.035), NK – (p = 0.041) and В lymphocytes (p = 0.038), and a significant increase in CD8+- (p = 0.02) and DP cells (p = 0.0018).Left-sided tumors showed a percentage decrease of CD45- cells expressing TLR4 and TLR8, compared to right-sided tumors, by 38% (p = 0.038) and 25% (p = 0.043).There was a decrease in the number of CD45+ cells expressing TLR2 and TLR4 in left-sided tumors by 54% (p = 0.035) and 33% (p = 0.04) respectively, than in right-sided tumors.The percent of CD45- cells expressing TLR4 in the perifocal tissues of left-sided tumors decreased by 61% (p = 0.031) in comparison to the corresponding tissues in right-sided tumors.The numbers of CD45+ cells expressing TLR2 and TLR4 were 81% (p = 0.02) and 87% (p = 0.018) lower respectively in the peritumoral tissues of left-sided tumors, compared to the corresponding tissues in right-sided tumors.Conclusion: The revealed characteristics of the local subpopulations of immunocompetent cells and the numbers of CD45+/- cells expressing TLRs depending on the tumor location on the right or left sides of the colon can serve as a prognosis of the disease clinical course and the choice of further treatment tactics

Вирус болезни Ньюкасла и иммунитет - эффективный альянс в борьбе против рака (обзор литературы)

Cancer is still the leading cause of death in developed countries. Oncolytic virus (OV) therapy is a promising new strategy for tumor growth inhibition. Despite the fact that the oncolytic function of some viruses was discovered in the last century, it has not been properly applied and recognized. The viruses of the Paramyxoviridae family, particularly Newcastle disease virus (NDV), are powerful oncolytic and immunostimulating agents non-pathogenic in humans. NDV is characterized by a selective infection and spread of the virus in tumor cells, direct cytopathic effect, and indirect induction of the innate and adaptive immune system of the host. However, intratumoral administration of OVs is not always possible and results in only local effect. There is an assumption that immune system cells can be used as possible carriers of OVs to provide temporary protection against immune system factors of the body. Dendritic cells (DCs) were the most effective cellular carriers among numerous types of immune cells evaluated in studies of the OV effect. In conclusion, the authors suggest that the use of OVs as an adjuvant for tumor antigens in the development and improvement of DC vaccine optimizes the development of antitumor immune response, STAT - signal transducer and activator of transcription.В настоящее время рак остается одной из ведущих причин смертности в развитых странах мира. Использование онколитических вирусов (ОВ) является перспективным возможным методом ингибирования опухолевого роста. Несмотря на то, что открытие онколитической функции ряда вирусов произошло еще в прошлом веке, использование ОВ до сих пор не нашло должного признания. Одни из наиболее многообещающих - вирусы семейства Paramyxoviridae, в частности вирус болезни Ньюкасла (ВБН), не являющийся патогенным для человека и обладающий некоторыми эффективными механизмами воздействия на опухолевые клетки и индукции иммунного ответа. Для ВБН характерны селективное инфицирование и распространение вируса в опухолевых клетках, прямой цитопатический эффект, а также косвенная индукция врожденного и адаптивного иммунного ответа хозяина. Однако внутриопухолевое введение ОВ не всегда является возможным и приводит лишь к локальному действию. Существует предположение, что клетки иммунной системы могут использоваться в качестве возможных носителей ОВ для обеспечения временной защиты от факторов иммунной системы организма опухоленосителя. В исследованиях действия ОВ самыми эффективными клеточными носителями среди многочисленных оцениваемых типов иммунных клеток являлись дендритные клетки (ДК). Таким образом, совместное действие ОВ и ДКВ является важным для взаимного потенцирования противоопухолевого эффекта обоих компонентов (вирусного и клеточного); получение таких продуктов представляется целесообразным с целью их дальнейшего клинического применения

Local cytokine levels as prognostic factors for early relapse of non-muscle-invasive bladder carcinoma

The aim of our study is to assess the local cytokine levels as prognostic factors for early relapse in NMIBC patients. 75 patients with NMIBC were enrolled in the study: 51 with primary NMIBC and 24 with initially recurrent NMIBC, LG and HG tumors were diagnosed in each group. Patients with primary NMIBC were monitored during 9 months after treatment: TURB and chemotherapy (No. 6). During TURB samples of tumors were taken, supernatants were obtained and tissue cytokine levels were measured (IL-1β, IL-6, IL-10, IL-18, TNFα, IFNγ, IL-8) by ELISA test. The results showed that in patients with primary NMIBC early relapses were diagnosed in 15 (46.8%) of LG tumors and in 11 (45%) of HG tumors matching that there was no difference depending upon tumor grade. In initially recurrent tumors of both LG and HG NMIBC the amounts of cytokines were maximal: in LG tumors they exceeded the primary ones from 7.1 (IFNγ) to 300 (IL-6) while in HG - from 2.0 (IL-10) to 9.7 (IL-6). The amounts of IL-1β, IL-6, IL-10, IFNγ, IL-8 were higher in those LG primary tumors which relapsed in 6-9 months compared to the ones which didn't, though their levels were much lower than in initially manifested relapse (from 2.6 times for IFNy to 150 times for IL-6). A similar trend, though not for all the same cytokines, was observed in HG tumors: tissue levels of IL-6, IL-10, IL-18 and TNFα were higher in tumors which relapsed in 6-9 months after treatment. The increase of 2 cytokines' levels were common for both LG and HG tumors (IL-6 and IL-10). This finding might be considered as a new prognostic factor of the early relapse. We conclude that relapse of LG and HG NMIBC is related to some immune mechanisms, namely to local hyperproduction of cytokines, especially IL-6 and IL-10, though IL-1β, IL-8, IFNγ could have an impact on LG and IL-18, TNFα — on HG tumors. Taking into account common signaling pathways of IL-6 and IL-10 like JAK/STAT, these transcription factors might be potential targets for new effective approaches to treatment

ИНДИВИДУАЛЬНЫЙ ПРОГНОСТИЧЕСКИЙ АЛГОРИТМ РИСКА ПРОГРЕССИРОВАНИЯ РАКА ПИЩЕВОДА ПОСЛЕ ХИРУРГИЧЕСКОГО ЛЕЧЕНИЯ

The development of laboratory criteria for predicting esophageal cancer (EC) prognosis is of great importance due to the need to achieve personalized approach to cancer treatment. Since the role of lymphocytic infiltration in EC remains controversial, our goal was to develop a prognostic algorithm for estimating the risk of esophageal squamous cell carcinoma progression, considering its lymphocytic microenvironment.Material and Methods. Tumor tissues were obtained from 40 EC patients during surgery; the tissues were homogenized, and lymphocyte subsets (Т-В-NK, T-reg) were determined by flow cytometry. A prognostic algorithm for calculating the risk of EC progression within 3 years was developed using discriminant analysis with the calculation of the three F functions: F0 , F6–12, F12–24, corresponding to the absence of the risk of EC progression during 3 years (F0 ); a high risk of EC progression during 6–12 months (F6–12); a high risk of EC progression during 12–24 months (F12–24) after surgery.Results. Only two factors showed the highest discriminant power, allowing us to consider the differences as statistically significant – CD3+CD4+ and T-reg cells in tumors. When dividing EC patients into groups based on the prediction of time to disease progression, coefficients were calculated and mathematical functions were determined for three discriminant functions (F0 , F6–12, F12–24) organized into a model. The F coefficient calculated for each patient allowed us to predict the risk of EC progression 6–12 and 12–24 months after surgery or the absence of disease progression within 3 years after surgery.Conclusions. The development of EC progression after surgery is apparently influenced by the lymphocytic microenvironment, predominantly by CD3+CD4+ and T-regs; their determination and inclusion in the prognostic algorithm can be important for personalized approach to the treatment of EC patients. Разработка лабораторных критериев прогнозирования течения рака пищевода (РП) является актуальной задачей современной онкологии в связи с необходимостью обеспечения персонализированного подхода к его лечению. Поскольку роль лимфоцитарной инфильтрации в течении и прогнозе РП остается дискуссионной, целью исследования явилась разработка прогностического алгоритма оценки риска прогрессирования плоскоклеточного рака пищевода на основании изучения показателей его лимфоцитарного микроокружения.Материал и методы. У 40 больных РП во время операции брали фрагмент опухоли, который гомогенизировали и методом проточной цитофлюориметрии определяли субпопуляции лимфоцитов (Т-В-NK, T-reg). Прогностический алгоритм расчета риска прогрессирования РП в течение 3 лет после операции был разработан методом дискриминантного анализа c вычислением трех функций – F0 , F6–12, F12–24, соответствующих заключениям об отсутствии риска прогрессирования РП в течение 3 лет (F0 ); о высоком риске прогрессирования в течение 6–12 мес (F6–12); о высоком риске прогрессирования заболевания в течение 12–24 мес (F12–24) после операции.Результаты. Показано, что наибольшей дискриминантной мощностью, позволяющей считать различия статистически значимыми, обладают только два показателя: количество CD3+CD4+ и T-reg клеток в опухоли. При разделении больных РП в зависимости от сроков прогнозируемого прогрессирования заболевания были рассчитаны коэффициенты и определены математические выражения для трех дискриминантных функций (F0 , F6–12, F12–24), организованные в модель. Коэффициент F, рассчитанный для каждого больного и представленный в разработанном нами индивидуальном автоматизированном окне в программе Excel, позволил прогнозировать риск прогрессирования рака пищевода через 6–12, 12–24 мес после операции или судить об отсутствии прогрессирования в течение 3 лет после операции.Заключение. В прогрессировании РП после операции, вероятно, играет роль лимфоцитарное микроокружение, а именно субпопуляции CD3+CD4+ и T-reg клеток, определение и включение которых в прогностический алгоритм может стать важной частью персонализированного подхода при лечении больных раком пищевода.

РЕЗУЛЬТАТЫ ПРИМЕНЕНИЯ СЕЛЕКТИВНОЙ АДСОРБЦИИ ЭНДОТОКСИНА ПРИ СЕПСИСЕ У ОНКОЛОГИЧЕСКИХ БОЛЬНЫХ

Objective: to study the clinical efficiency of using selective lipopolysaccharide (LPS) adsorption in postoperative gram negative sepsis in cancer patients.Subjects and methods. Examinations were made in 47 patients (11 women and 36 men) aged 47 to 84 years, who had been operated on for cancer and whose postoperative period had been complicated by gramnegative sepsis. The patients were divided into 2 groups: 1) 15 patents who received standard therapy (a control group); 2) 32 who had LPS adsorption using immobilized polymyxin B (a study group).Results. Upon completion of the selective LPS adsorption program, there was regression of the clinical signs of sepsis, statistically significantly lower peripheral blood leukocyte and neutrophil levels, and better blood biochemical parameters in 87.5% of cases. High baseline endotox in activity decreased from >0.6 to <0.4 units in 89% of the patients. After the final session of LPS adsorption, the need for vasopressor support reduced due to hemodynamic profile optimization. After selective endotoxin adsorption cycles, 15 of 26 cases did not need to continue organ replacement therapy. Twentyeightday mortality rates in the study and control groups were 25.0 and 53.3%, respectively.Conclusion. Incorporation of LPS adsorption into a set of intensive therapy for gramnegative sepsis is pathogenetically substantiated and can effectively abolish the manifestations of the systemic effects of bacterial endotoxin. The early and timely use of LPS adsorption provides inhibition of an initiating stimulus, which makes it possible to prevent the progression of a septic process and the development of severe sepsis and septic shock and improves the results of therapy in cancer inpatients.Цель. Изучить клиническую эффективность применения селективной ЛПСадсорбции при грамотрицательном сепсисе, развившимся в послеоперационном периоде у онкологических больных.Материал и методы. Обследовано 47 больных в возрасте от 47 до 84 лет (11 женщин и 36 мужчин), подвергнутых хирургическому вмешательству по поводу онкологических заболеваний, послеоперационный период которых осложнился развитием грамотрицательного сепсиса. Больные были разделены на 2 группы — контрольную и основную. Контрольная группа — 15 человек, получавших стандартную терапию, основная группа — 32, которым была применена ЛПСадсорбция с иммобили зированным полимиксином В. Результаты. После завершения программы селективной ЛПСадсорбции в 87,5% случаев наблюдали регресс клинических признаков сепсиса, статистически значимое снижение уровня лейкоцитов и нейтрофилов в периферической крови, улучшение биохимических показателей крови. У 89% больных регистрировали снижение исходно высоких показателей активности эндотоксина от >0,6 ед. до <0,4 ед. После заключительного сеанса ЛПСадсорбции отмечено снижение потребности в вазопрессорной поддержке в связи с оптимизацией «гемодинамического профиля». В 15 из 26 случаев после проведения курсов селективной адсорбции эндотоксина необходимости в продолжении органозаместительной терапии не было. Летальность (28дневная) в основной группе составила 25,0%, в контрольной — 53,3%.Заключение. Включение в комплекс интенсивной терапии грамотрицательного сепсиса метода ЛПСадсорбции является патогенетически обоснованным и позволяет эффективно купировать проявления системного воздействия бактериального эндотоксина. Раннее и своевременное применение метода ЛПСадсорбции обеспечивает ингибирование инициирующего стимула, что позволяет предупредить прогрессирование септического процесса, развитие тяжелого сепсиса и септического шока, улучшает результаты лечения госпитального периода онкологических больных

Гуманизированные животные как модели экспериментальной онкологии (обзор литературы)

The humanization of immunodeficient animals allows us to study the growth of xenografts of human malignant tumors and their response to therapeutic effects, taking into account processes in the immune system and tumor zone, which have a significant impact on oncogenesis and the effectiveness of antitumor therapy. Such experimental models are currently considered as the most advanced tool in the development of personalized antitumor treatment. The lines of immunodeficient animals most commonly used for the transplantation of mature and stem human immune cells have been characterized. The main sources of human immune cells when implementing the hu-pbl and hu-cd34+ models, as well as the blt model (as an option to the cd34+ model) are described. The basic procedures necessary for reproducing each model, their modification in adult and newborn animals are outlined as well as the parameters of immunosuppressive radiation exposure, preceding the transplantation of human hematopoietic stem cells. The main results of the humanization of immunodeficient animals and examples of the use of these models for the purposes of fundamental and clinical oncology are described. The main problems of this direction are discussed. The review is based on an analysis of the literature presented in the scopus, web of science, medline, risc and others databases over the past 7 years (over 80 % of literature sources, with more than over 50 % of studies published over the last 3 years).Гуманизация иммунодефицитных животных позволяет исследовать рост ксенотрансплантатов злокачественных опухолей человека и их реакцию на лечебные воздействия с учетом процессов в иммунной системе и зоне опухоли, оказывающих значительное влияние на онкогенез и эффективность противоопухолевой терапии. Такие экспериментальные модели в настоящее время рассматриваются в качестве наиболее совершенного инструмента при разработке персонализированного противоопухолевого лечения. В обзоре охарактеризованы линии иммунодефицитных животных, используемых для трансплантации зрелых и стволовых клеток иммунной системы человека, описаны основные источники получения иммунных клеток человека при реализации Hu-pBl и Hu-cd34+ моделей, обозначены основные процедуры, необходимые для воспроизведения каждой модели, их модификации у взрослых и новорожденных животных, а также параметры иммуносупрессивного лучевого воздействия, предваряющего трансплантацию гемопоэтических стволовых клеток человека. Описаны основные результаты гуманизации иммунодефицитных животных и примеры использования этих моделей для целей фундаментальной и клинической онкологии. Обсуждаются основные проблемы данного направления. Обзор составлен на основе анализа литературы, представленной в базах данных scopus, Web of science, medline, РИНЦ и др. за последние 7 лет (более 80 % источников, при этом более 50 % работ были опубликованы за последние 3 года)

Метаболизм триптофана при различном эффекте иммунотерапии немелкоклеточного рака легкого ингибиторами PD-1 / PD-L1

Introduction. In the structure of cancer incidence, lung cancer ranks first among men. In order to study the molecular mechanisms of the initiation and progression of lung cancer, it is necessary to study not only the tumor cells themselves, but also the features of the systemic tryptophan metabolism. Tryptophan catabolites, being to a large extent product of the metabolic activity of the intestinal microbiota, can affect the effectiveness of immunotherapy with checkpoint inhibitors. The kynurenine pathway of tryptophan metabolism is intensified in the body of cancer patients; its products have a pro-oncogenic and immunosuppressive effect, which may hinder the effectiveness of immunotherapy.Objective – to study the dynamics of changes in various metabolites of tryptophan metabolism in the blood serum and feces of patients with non-small cell lung cancer with various effects of immunotherapy with inhibitors of PD-1 (programmed cell death receptor 1) / PD-L1 (programmed cell death receptor 1 ligand).Materials and methods. The study included blood serum and stool samples obtained from 20 patients with non-small cell lung cancer treated with PD-1 / PD-L1 inhibitors. Using high-performance liquid chromatography with mass spectrometric analysis, the levels of 13 tryptophan metabolites were assessed in patients with various effects of immunotherapy. The significance of differences between the samples was assessed using a nonparametric method according to the Mann – Whitney test. They were considered statistically significant at p <0.05.Results. In fecal analyzes of patients in whom a positive effect of immunotherapy was observed, baseline levels of 5-hydroxyindole acetate and quinolinic acid were lower than in patients with tumor progression. Positive clinical dynamics was accompanied by a decrease in the content of indole-3-lactate, kynurenine and indole-3-carboxaldehyde in the feces of patients. In the serum of patients with a positive response, the initial content of 5-hydroxyindole acetate, indole-3-acetate, indole-3-butyrate and quinoline acid was lower than in patients with progression of non-small cell lung cancer. A positive response to immunotherapy was characterized by an increase in the levels of indole-3-butyrate and indole-3-propionate, and a negative response was not accompanied by statistically significant changes in the studied tryptophan metabolites.Conclusion. Profiling tryptophan metabolites in feces and serum of patients with non-small cell lung cancer can be used to predict the effectiveness of immunotherapy with PD-1 / PD-L1 inhibitors.Введение. В структуре онкологической заболеваемости рак легкого занимает 1-е место среди мужчин. С целью изучения молекулярных механизмов инициации и прогрессирования рака легких необходимо исследовать не только сами опухолевые клетки, но и особенности системного метаболизма триптофана. Катаболиты триптофана, будучи в большой степени продуктами метаболической активности микробиоты кишечника, могут влиять на эффективность проведения иммунотерапии ингибиторами контрольных точек. Кинурениновый путь метаболизма триптофана интенсифицируется в организме онкологических пациентов, его продукты имеют проонкогенное и иммуносупрессивное действие, что может препятствовать эффективности иммунотерапии.Цель исследования – изучение динамики изменений различных метаболитов триптофанового обмена в сыворотке крови и кале больных немелкоклеточным раком легкого при различных эффектах иммунотерапии ингибиторами PD-1 (рецептора программируемой клеточной гибели 1) / PD-L1 (лиганда рецептора программируемой клеточной гибели 1).Материалы и методы. В исследование были включены образцы сыворотки крови и кала, полученные от 20 больных немелкоклеточным раком легкого, получавших ингибиторы PD-1 / PD-L1. С помощью высокоэффективной жидкостной хроматографии с масс-спектрометрическим анализом проведена оценка уровней 13 метаболитов триптофана у больных с различными эффектами иммунотерапии. Достоверность различий между выборками оценивали с помощью непараметрического метода по критерию Манна–Уитни. Они считались статистически значимыми при р <0,05.Результаты. В анализах кала пациентов, у которых наблюдали положительный эффект от иммунотерапии, исходные уровни 5-гидроксииндолацетата и хинолиновой кислоты были ниже, чем у больных с прогрессированием опухоли. Положительная клиническая динамика сопровождалась снижением содержания индол-3-лактата, кинуренина и индол-3-карбоксальдегида в анализах кала больных. В сыворотке пациентов с положительным ответом исходное содержание 5-гидроксииндолацетата, индол-3-ацетата, индол-3-бутирата и хинолиновой кислоты оказалось ниже, чем у пациентов с прогрессированием немелкоклеточного рака легкого. Положительный ответ на иммунотерапию характеризовался повышением уровней индол-3-бутирата и индол-3-пропионата, а отрицательный – не сопровождался статистически значимыми изменениями исследованных триптофановых метаболитов.Заключение. Профилирование метаболитов триптофана в кале и сыворотке больных немелкоклеточным раком легкого может быть использовано для прогнозирования эффективности иммунотерапии ингибиторами PD-1 / PD-L1