The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms of interaction and research prospects Текст научной статьи по специальности «Клиническая медицина»

South Russian Journal of Cancer. 2024. Vol. 5, No. 4. P. 58-70 4.0

https://doi.org/10.37748/2686-9039-2024-5-4-7

https://elibrary.ru/jbckse

South Russian

Journal of Cancer REVIEW

Южно-Российский

онкологический журнал

Vol. 5

No. 4, 2024 The role of tumor stem cells and the immune microenvironment

in the pathogenesis of lung cancer: mechanisms of interaction

and research prospects

D. A. Kharagezov, A. A. Antonyan,E. Yu. Zlatnik, A. B. Sagakyants, E. A. Mirzoyan,

T. G. Ayrapetova, I. A. Leyman, A. G. Milakin, O. N. Stateshny, K. D. Iozefi,

M. A. Homidov, E. A. Alekseev

National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

 [email protected]

ABSTRACT

Despite significant advances in the treatment of malignant neoplasms, the issue of therapy resistance mediated by cancer

stem cells (CSCs) necessitates the development of new treatment strategies. Studying the role of CSCs and the immune mi-

croenvironment in the pathogenesis of cancer, particularly non-small cell lung cancer (NSCLC), is a pressing issue in modern

oncology. This paper is based on an extensive analysis of recent research and aims to study the mechanisms underlying the

development of NSCLC.

The origin of CSCs, their markers, and the main signaling pathways involved in regulating their activity are considered. Special

attention is paid to the influence of CSCs on the progression of lung cancer and the mechanisms underlying their therapy-

mediated resistance. Various approaches to treating lung cancer targeting CSCs, focusing on targeted therapy aimed at

specific molecular targets, are highlighted.

The important role of the tumor immune microenvironment in the pathogenesis of lung cancer and its impact on CSCs is

emphasized. Mechanisms of immune response regulation in tumors and the potential use of immunotherapy to improve lung

cancer treatment outcomes are discussed. The article also reviews modern diagnostic and treatment methods, including

molecular- genetic and immunohistochemical approaches.

This paper work represents a review of current knowledge on the mechanisms of lung cancer development and is significant

for understanding tumor biology and developing new treatment methods. The need for an interdisciplinary approach and com-

prehensive use of modern diagnostic and therapeutic methods to improve the prognosis and survival rates of NSCLC patients

is emphasized. Special attention is given to the prospects of using combined therapeutic approaches, including targeted drugs

and immunotherapy, aimed at suppressing CSC activity and modifying the tumor microenvironment.

In conclusion, a deep understanding of the molecular mechanisms regulating CSC activity and their interaction with the tumor

microenvironment opens new opportunities for developing effective treatment strategies. This review underscores the need

for further research in this area to ensure more successful treatment and improved quality of life for lung cancer patients.

Keywords: cancer stem cells, immune microenvironment, lung cancer, non-small cell lung cancer, therapy resistance,

targeted therapy, immunotherapy

For citation: Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N.,

Iozefi K. D., Homidov M. A., Alekseev E. A. The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms

of interaction and research prospects. South Russian Journal of Cancer. 2024; 5(4): 58-70. https://doi.org/10.37748/2686-9039-2024-5-4-7,

https://elibrary.ru/jbckse

For correspondence: Artur A. Antonyan – PhD student of the 1st year, National Medical Research Centre for 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/0000-0001-6449-7026

ResearcherID: JWQ-0734-2024

Funding: this work was not funded

Conflict of interest: the authors declare that there are no obvious and potential conflicts of interest associated with the publication of this article

The article was submitted 08.06.2024; approved after reviewing 30.10.2024; accepted for publication 13.11.2024

© Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N., Iozefi K. D.,

Homidov M. A., Alekseev E. A., 2024

58

Южно-Российский онкологический журнал. 2024. Т. 5, № 4. С. 58-70

https://doi.org/10.37748/2686-9039-2024-5-4-7

https://elibrary.ru/jbckse

3.1.6. Онкология, лучевая терапия

ОБЗОР

Роль опухолевых стволовых клеток и иммунного микроокружения в патогенезе рака

легкого: механизмы взаимодействия и перспективы исследований

Д. А. Харагезов, А. А. Антонян, Е. Ю. Златник, А. Б. Сагакянц, Э. А. Мирзоян, Т. Г. Айрапетова, И. А. Лейман,

А. Г. Милакин, О. Н. Статешный, К. Д. Иозефи, М. А. Хомидов, Э. А. Алексеев

ФГБУ «Национальный медицинский исследовательский центр онкологии» Министерства здравоохранения Российской Федерации,

г. Ростов-на-Дону, Российская Федерация

 [email protected]

РЕЗЮМЕ

Несмотря на значительные успехи в лечении злокачественных новообразований, проблема резистентности к терапии,

опосредованной опухолевыми стволовыми клетками (ОСК), диктует необходимость разработки новых стратегий

лечения. Изучение роли ОСК и иммунного микроокружения в патогенезе рака, особенно немелкоклеточного рака

легкого (НМРЛ), является актуальным вопросом современной онкологии. Настоящая работа основана на обшир-

ном анализе последних исследований и направлена на изучение механизмов, лежащих в основе развития НМРЛ.

Рассматривается происхождение ОСК, их маркеры и основные сигнальные пути, участвующие в регуляции активности

данного пула клеток. Особое внимание уделяется влиянию ОСК на прогрессирование рака легкого и механизмам,

обусловливающим устойчивость к терапии. Освещаются различные подходы к лечению рака легкого, ориентиро-

ванные на ОСК, с акцентом на таргетную терапию, направленную на специфические молекулярные мишени.

Отмечается важная роль иммунного микроокружения опухоли в патогенезе рака легкого и его влияния на ОСК.

Обсуждаются механизмы регуляции иммунных реакций в опухоли и потенциал использования иммунотерапии для

улучшения результатов лечения рака легкого. В статье также рассматриваются современные методы диагностики

и лечения, включающие молекулярно- генетические и иммуногистохимические подходы.

Работа представляет собой обзор современных знаний о механизмах развития рака легкого и имеет важное зна-

чение для понимания биологии опухолей и разработки новых методов лечения. Подчеркивается необходимость

междисциплинарного подхода и комплексного использования современных диагностических и терапевтических

методов для улучшения прогнозов и выживаемости пациентов с НМРЛ. Особое внимание уделено перспективам

использования комбинированных терапевтических подходов, включающих таргетные препараты и иммунотерапию,

направленные на подавление активности ОСК и модификацию опухолевого микроокружения.

В заключение, глубокое понимание молекулярных механизмов, регулирующих деятельность ОСК, и их взаимодей-

ствие с микроокружением опухоли открывает новые возможности для разработки эффективных стратегий лечения.

Данный обзор подчеркивает необходимость дальнейших исследований в этой области, чтобы обеспечить более

успешное лечение и повышение качества жизни пациентов с раком легкого.

Ключевые слова: опухолевые стволовые клетки, иммунное микроокружение, рак легкого, немелкоклеточный рак

легкого, резистентность к терапии, таргетная терапия, иммунотерапия

Для цитирования: Харагезов Д. А., Антонян А. А., Златник Е. Ю., Сагакянц А. Б., Мирзоян Э. А., Айрапетова Т. Г., Лейман И. А., Милакин А. Г.,

Статешный О. Н., Иозефи К. Д., Хомидов М. А., Алексеев Э. А. Роль опухолевых стволовых клеток и иммунного микроокружения в патогенезе рака

легкого: механизмы взаимодействия и перспективы исследований. Южно-Российский онкологический журнал. 2024; 5(4): 58-70.

https://doi.org/10.37748/2686-9039-2024-5-4-7, https://elibrary.ru/jbckse

Для корреспонденции: Антонян Артур Андрясович – аспирант 1-го года обучения, ФГБУ «Национальный медицинский исследовательский центр

онкологии» Министерства здравоохранения Российской Федерации, 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/0000-0001-6449-7026

ResearcherID: JWQ-0734-2024

Финансирование: финансирование данной работы не проводилось

Конфликт интересов: все авторы заявляют об отсутствии явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи

Статья поступила в редакцию 08.06.2024; одобрена после рецензирования 30.10.2024; принята к публикации 13.11.2024

59

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 58-70

Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N., Iozefi K. D.,

Homidov M. A., Alekseev E. A. The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms of interaction

and research prospects

INTRODUCTION ing molecular genetic and immunohistochemical

[3, 4], as well as the possibility of using them as

Lung cancer is one of the main problems of targets for therapy [5, 6]. Currently, the noticeable

modern oncology, and it is hoped that progress in increase in the number of publications on CSC re-

treatment can be achieved by improving our under- search indicates the relevance of this topic in the

standing of the molecular basis and biology of the scientific community. The valuable scientific data

tumor, especially at the level of cells that initiate provided by the literature on the mechanisms of

the tumor process. The most common type of lung oncogenesis and the prospects for the treatment

cancer is its non–small cell variants (NSCLC), which of lung cancer based on them determine the need

account for about 90 % of lung cancers, the rest for a more in-depth scientific analysis of the role

are small cell lung cancer (SCLC). NSCLC includes of CSC in the pathogenesis of NSCLC. The modern

three histological subtypes: adenocarcinoma, squa- literature provides numerous data on the biology of

mous cell carcinoma and large cell carcinoma. In CSC, their role in the progression of NSCLC, and the

most patients with NSCLC, the diagnosis is made development of its resistance to various treatment

at a late stage, when various treatment methods methods [5, 6].

are ineffective [1]. The purpose of the review is to analyze the cur-

In 2015, a  new classification of lung tumors rent level of scientific knowledge about the role of

was proposed by the World Health Organization CSC in NSCLC and the clinical use of these data. The

[2], which includes appropriate histopathological main focus is on identifying the key mechanisms

and immunohistochemical data, which can be ob- of these cells' involvement in oncogenesis, their

tained not only from surgical material, but also from interaction with the immune microenvironment of

biopsies and cytological material [1, 2]. This is es- the tumor, as well as developing treatment strate-

pecially important due to the fact that about 70 % gies aimed at CSC in NSCLC. The data obtained as

of patients with lung cancer are in the late stages a result of the review, in our opinion, can serve as

of the disease, when the process is considered a foundation for further research and development

inoperable [1, 2]. For resectable lung tumors, it is of promising treatments for NSCLC.

important to diagnose tumors in situ and minimal-

ly invasive operations, in which the probability of CSC in NSCLC: origin, markers, signaling

recurrence-free survival after complete resection pathways, role in progression

is 100 % [2]. According to modern concepts, cancer stem

However, in most cases, clinicians are dealing cells (CSC) arise from normal tissue-s pecific stem

with locally advanced NSCLC, the recurrence and cells of the original tissues; their main function is

generalization of which, even after the successful to maintain and regulate the processes of growth,

surgical stage of treatment, is the main cause of development and repair of tissues in the body. CSC

death. These processes, as well as the develop- are capable of self-renewal, differentiation [7] and

ment of chemo- and radioresistance, according to proliferation [8] and cause such adverse properties

modern concepts, are not least associated with the as: chemoresistance, recurrence and metastasis

presence of stem cells (CSC) in the tumor, a minor [7]. As a rule, a high number of CSC is associated

subpopulation that ensures their preservation and with aggressive tumor growth and unfavorable clin-

survival. Since CSC biomarkers can be used for ical outcomes [8], although CSC themselves have

diagnosis, targeted therapy and prediction of the low proliferative activity. Reviews of CSC note their

course of the disease, assessing the significance common characteristics for various malignant tu-

of known ones and searching for new ones seems mors involved in the development of resistance to

relevant. Potential markers for NSCLC include sur- therapy and are devoted to the development of new

face markers (CD44, CD133, EpCAM, ABCG2), as therapeutic strategies [7–10].

well as intracellular markers (ALDH, SOX2). The Inducing epithelial-m esenchymal transition tran-

literature discusses not only their diagnostic and scription factors (EMF-FT), including SNAIL and

prognostic significance in NSCLC, but also the SLUG, and induced by signaling pathways such as

most informative methods of determination, includ- TGFß, Wnt and Notch, tumor cells begin to show

60

Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 58-70

Харагезов Д. А., Антонян А. А., Златник Е. Ю., Сагакянц А. Б., Мирзоян Э. А., Айрапетова Т. Г., Лейман И. А., Милакин А. Г., Статешный О. Н., Иозефи К. Д.,

Хомидов М. А., Алексеев Э. А. Роль опухолевых стволовых клеток и иммунного микроокружения в патогенезе рака легкого: механизмы взаимодействия

и перспективы исследований

distinctive signs of CSC: oncogenicity, invasiveness For example, Eramo et al. The presence of CD133

and resistance to basic treatments [11]. Other com- in NSCLC was detected in a small amount of less

mon signaling pathways involved in CSC include than 1 % [16]. CD133+ cells were able to form tu-

Hedgehog (Hh), PI3K/Akt/mTOR, and NF-κβ [12]. mor spheroids in vitro in about 30 % of cases when

Although many of these pathways are also observed grown in a serum-free medium; CD133+ cells derived

in normal cells and non-stem cancer cells [13], their from tumor spheroids are capable of inducing tu-

altered activity, along with certain membrane mark- mors with histological signs similar to those of the

ers and transcription factors, is a distinctive feature original tumor when inoculated to immunodeficient

of CSC. Some of these characteristics, such as the mice [16]. Moreover, CD133+ cells show resistance

high expression of CD44+, CD133+, ATP-binding to chemotherapy due to the expression of high levels

cassette transporters (ABC), epithelial cell adhe- of ATP-binding G2 [17].

sion molecules (EpCAM), aldehyde dehydrogenase CD44 (P-glycoprotein 1), a transmembrane type

1 (ALDH1), and transcription factors Oct4 and Sox2, I glycoprotein, belongs to the family of cell adhe-

are common to CSC in many forms of cancer [11]. sion molecules, is a receptor for hyaluronic acid,

Recognition of such similarities may reveal new when interacting with which cell detachment, me-

therapeutic possibilities for influencing common tastasis and invasion can occur. CD44 is respon-

markers or pathways, and thus contribute to the sible for various functions such as cell differen-

development of effective treatments targeting CSC. tiation, survival, migration, proliferation. Studies

Identification of the origin of tumor stem cells have demonstrated that CD44 plays a crucial role in

(CSC) in the lungs is a difficult task, since the epi- ensuring self-renewal and resistance to apoptosis

thelium of the trachea and bronchioles is at rest and of CSC [11, 18]. Mutations in the key regulator of

has low proliferative activity [11]. The most com- apoptosis, the p53 gene, may be associated with

mon hypothesis states that CSC arise from normal high CD44 expression in pancreatic cancer [19].

tissue-s pecific stem cells. Squamous cell lung can- CD44+ adenocarcinoma and squamous cell lung

cer originates from the basal cells of the proximal cancer cells demonstrate the ability to form spher-

respiratory tract (trachea and bronchi) [12]. Clara oid bodies in vitro [20] and lead to tumor formation

cells in squamous cell lung cancer are also able in vivo when administered to mice with immuno-

to exhibit stem properties, and adenocarcinoma is deficiency [14, 21].

associated with normal stem cells from the junction Studies have shown that in lung cancer, CD44

of bronchoalveolar ducts [12]. expression in NSCLC cells is higher than in SCLC,

Although the available knowledge about the func- and in squamous cell lung cancer its highest level

tions of lung CSC is limited, a number of CSC mark- was observed [22]. CD44 regulates several signal-

ers belonging to differentiation clusters (CD) have ing pathways contributing to cancer progression,

been proposed. Many studies have confirmed the including Notch, Hedgehog (HH), Wnt, STAT3, Hip-

presence of the following molecules on lung CSC: po, JNK and RhoGTPase, and It is a co-receptor

CD133, CD44, CD90, EpCAM, CXCR4 [14, 15]. How- involved in the signaling pathways of tyrosine ki-

ever, it should be noted that impaired expression of nase receptors [23, 24]. In addition, CD44 is a key

these markers is characteristic not only of NSCLC, mediator of adhesion between endothelial cells,

but also of many types of cancers. while playing an important role in pathological an-

EpCAM is a  transmembrane glycoprotein ex- giogenesis [25]. CD44 can also promote tumor pro-

pressed in most human carcinomas; high expression liferation and evasion of immunity by stimulating

is noted in rapidly proliferating tumors of epithelial PD-L1 expression on the surface of tumor cells [26].

origin [12]. Cells coexpressing CD44 and ALDH, which is typ-

CD133 is a marker widely used to identify stem ical for squamous cell lung cancer, always exhibit

cells in both tumor and normal tissues. The CD133 a high ability for self-renewal, increased migration

transcription process is regulated by five promot- and tumorigenicity [27].

ers, and the 5P5 promoter plays a crucial role in CD90 is a glycoprotein anchored by glycosylphos-

CD133 expression in the CSC [16]. Some studies phatidylinositol, expressed mainly in leukocytes and

have characterized CD133+ cells in NSCLC [11, 15]. participates in cell-matrix and cell-cell interactions.

61

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 58-70

Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N., Iozefi K. D.,

Homidov M. A., Alekseev E. A. The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms of interaction

and research prospects

Although CD90 is known as a marker for various [34]. The organoid culture method allows CSC to

types of CSC, its potential role as a marker for NS- be propagated in vitro, reflecting the complexity of

CLC has not yet been fully described [11, 28]. It has tumor formation using tumor tissues. Moreover,

been reported that CD44 and CD90 coexpressed the culture of organoids allows for the functional

CSC can be detected in primary pancreatic cancer analysis of CSC, including their genetic engineering

cell lines [19]. Mutations activating CD90 expres- using CRISPR/Cas9-mediated genome editing [35].

sion are not described in the literature, however, in Organoids obtained from the patient can be used to

a mouse model it has been shown that DNA meth- identify signs of CSC resistance to treatment. Most

ylation plays a role in stimulating the expression organoid models for cancer research are applica-

of this molecule. Serial xenotransplantation of Ep- ble to adenocarcinomas of different localizations

CAM+CD90+ NSCLC cells (adenocarcinoma and [36]. However, as the understanding of the mech-

squamous cell carcinoma) to mice with immunode- anisms of tumor development expands, organoids

ficiency revealed rapid growth of these cells during may become a more widely used tool [36]. Thus, in

heterotopic grafting [14]. combination with other in vivo experiments, such

CXCR4 is a chemokine receptor present on the as xenotransplantation of CSC, organoid cultures,

surface of hematopoietic stem cells involved in the human CSC have high potential to improve under-

formation of premetastatic niches in the bone mar- standing of cancer biology [37].

row [29]. The CXCR4/CXCL12 pathway plays a role

in tumor metastasis, induction of angiogenesis, and CSC-mediated resistance to treatment and the

development of resistance to apoptosis. Moreover, possibility of overcoming it

CXCR4 is present on circulating tumor cells released Drug resistance has been described as one of the

from tumors into peripheral blood, which induces most serious problems in the treatment of cancer,

their spread to distant CXCL12-positive sites [30]. while the multidrug resistance of CSC, which ensures

The expression of CXCR4 is regulated by the nuclear the chemoresistance of the tumor as a whole, is

respiratory factor NRF, a mutation in which can lead considered the main reason for the ineffectiveness

to higher expression of CXCR4 [31]. CXCR4+ cells of chemotherapy [38]. The mechanisms that cause

isolated from NSCLC lines exhibited the properties chemoresistance include ABC transporters, pumps

of CSC in vitro: they formed tumor spheroids, had for efflux of chemotherapy drugs and ALDH1 [38].

the ability to self-renew, and demonstrated radiation CSC radioresistance develops due to the inhibi-

resistance [32]. tion of apoptosis through the synthesis of antiapop-

Taking into account the described properties of totic proteins, increased DNA repair and the ability

CSC, their determination in tumors, in particular lung to remove free radicals, slowing down the kinetics

tumors, is an urgent scientific and clinical task [11, 33]. of the cell cycle, and transformation of non-stem

Due to the fact that CSC markers can also be tumor cells into CSC [39].

expressed on normal stem cells necessary for It is believed that the resistance of CSC to tra-

self-renewal and tissue regeneration, the belong- ditional radiation therapy and chemotherapy is as-

ing of stem cells to tumor cells can be determined sociated with the activation of various signaling

not only by the expression of membrane mark- pathways in them, such as: Wnt, Notch and Hedge-

ers, transcription factors and signaling pathways, hog, which are involved in increasing oncogenicity

but also by the results of some functional tests, and tumor invasiveness [40]. Currently, there is in-

which, despite their certain complexity, They are creasing evidence that these pathways are being

informative, especially for research purposes, as deregulated and mutated in the CSC [41]. Aberrant

well as for conducting preclinical trials of potential Wnt signaling is found in many cancers, including

drugs aimed at CSC. In addition to the mentioned NSCLC, especially adenocarcinomas [42], in which

spheroid formation test, organoids obtained from Wnt-reactive cells demonstrated proliferative po-

patients with NSCLC can become a tool for such tential and progression, which suggests that they

studies, due to their ability to recreate the tissue possess the characteristics of CSC [42]. A growing

architecture and maintain genomic changes in number of publications confirm the association of

primary tumors during long-term in vitro growth abnormal regulation of Notch signaling with vari-

62

Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 58-70

Харагезов Д. А., Антонян А. А., Златник Е. Ю., Сагакянц А. Б., Мирзоян Э. А., Айрапетова Т. Г., Лейман И. А., Милакин А. Г., Статешный О. Н., Иозефи К. Д.,

Хомидов М. А., Алексеев Э. А. Роль опухолевых стволовых клеток и иммунного микроокружения в патогенезе рака легкого: механизмы взаимодействия

и перспективы исследований

ous types of malignant neoplasms, including NS- tance. The CSC associated with these processes are

CLC. The Notch signaling pathway plays a role in considered in the literature as a promising target [46].

stem cell maintenance in NSCLC; aberration in this Three main approaches to CSC targeting have

pathway may lead to an increase in the number of been proposed: identification of new CSC biomark-

CSC resistant to platinum drug therapy [42]. It was ers, modification of their microenvironment, and

reported that the increased activity of Notch was sensitization to traditional medicines [8]. Combined

associated with the formation of tumor spheroids in treatment methods have been found to be the most

vivo [40]. The same authors associate Notch activity effective [8, 9, 13–15]. Makena et al. Other thera-

with a worse prognosis in patients with adenocarci- peutic approaches have been investigated, including

noma, which suggests a potential role of inhibition therapies that target dormant CSC and immunother-

of Notch activity as a new therapeutic approach [41]. apy, but noted that additional research is needed in

In NSCLC, the Hedgehog pathway is closely related these new areas [8]. Dongre and Weinberg proposed

to CSC [41, 42] and is involved in the formation of inducing reverse EMF as a potential therapeutic strat-

tumor drug resistance to targeted, chemo- and ra- egy, representing promising approaches to reduce

diation therapy [42]. the number of CSC inside tumors and increase their

Some approaches to overcoming resistance me- sensitivity to various types of treatment, including

diated by OSC are also described in the literature. chemotherapy, radiotherapy and immunotherapy [10].

Some combinations of chemo- and targeted drugs It is known that chelation of intracellular iron is

have the property of inhibiting OSC in NSCLC, for one of the targets of exposure to CSC, due to its

example, the combination of trifluorperazine with ability to successfully restrain cell proliferation, as

gefitinib or cisplatin reduces the regulation of CD133 has been demonstrated in studies on models of

and CD44, reducing drug resistance and increasing breast and pancreatic cancer. However, despite

the response to therapy [43]. these encouraging data, the efficacy and mecha-

It was found that the miR-29c tumor suppressor nisms of action of iron chelation in the context of

is significantly suppressed in radioresistant NSCLC squamous cell lung cancer remain poorly under-

CSC, but this resistance was overcome by restoring stood, emphasizing the need for further research

its expression, activating apoptosis, and suppress- in this area [47].

ing the regulation of Bcl-2 and Mcl-1 target genes In the literature, increasing attention is being paid

by this suppressor [44]. to the role of miRNAs and long non-coding RNAs

Yin and colleagues [45] conducted a study in (lncRNAs) in the regulation of transcription fac-

which they found that certain cells in the lungs, tors and pathways present in CSC [48]. It is known

called bronchoalveolar stem cells, transform into tu- that the miR-17–92 cluster, acting as a stimulator

mor stem cells due to two factors: the lack of a pro- of tumor growth, also has a noticeable effect on

tein that usually protects the cell from becoming the development of lung cancer, which leads to the

a tumor (Gprc5a), and exposure to nicotine- derived study of the relationship between microRNAs and

substances. These cells have a set of special mark- tumor development, definitely emphasizing their

ers (SPA+, CC10+, EGFR+, Abcg2+), thanks to which important role in cancer biology. lncRNAs control

they can be updated. The researchers also found gene expression and are involved in the mainte-

that cancer can develop not only from these stem nance and reproduction of CSC by activation of the

cells, which underscores the need to study different Wnt/β-catenin and IL6/STAT3 signaling pathways.

cell types to understand the mechanisms of lung Consequently, lncRNAs can be used as predictors

cancer development [45]. of an unfavorable prognosis for cancer patients

and, thus, can play a major role in the eradication

Approaches to the treatment of NSCLC of CSC [48].

targeted at CSC It has been repeatedly noted in the literature that

The development of drugs for targeted therapy of the acquisition of "stemness" by NSCLC tumors

oncological diseases is a consequence of the dis- is a negative prognostic factor of survival. Loss

covery of specific molecular genetic targets and re- of PTEN expression, for example, has important

ceptors responsible for progression and chemoresis- consequences for the NSCLC, and is also an inde-

63

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 58-70

Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N., Iozefi K. D.,

Homidov M. A., Alekseev E. A. The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms of interaction

and research prospects

pendent prognostic factor for the overall surviv- of tolerance [52]. CSC can also contribute to the

al of patients with NSCLC [49]. Similarly, patients creation of an immunosuppressive environment.

with stage IIIB/IV NSCLC with tumors enriched Some studies have demonstrated that CSC de-

with CD133+ lung cancer stem cells tend to have rived from various solid tumors, including glio-

a shorter progression-free survival after platinum blastoma multiforme and melanoma, secrete

chemotherapy [16]. various immunosuppressive cytokines such as

Nevertheless, a serious problem is the identifica- IL-13, IL-10, TGF-β, GDF-15, PGE2 and galectin-3.

tion of "silent" CSC, i. e., those that do not express These cytokines can protect the tumor microen-

well-known markers by which they can be identified. vironment from effector immune cells. CSC can

Conversely, many surface markers of CSC, such as induce differentiation of mature DC or Treg by

r2R4 and CD34, are also expressed by normal em- transforming growth factor beta (TGF-β) [51]. The

bryonic or adult stem cells, while others, such as tumor microenvironment (MO, TME) is an area

CD44 variants, are widely expressed even in normal that can simultaneously regulate tumor develop-

cells of various tissues [16]. Thus, the identification ment and cell self-renewal. CSC can contribute

of more specific markers of OSC remains a key goal to the development of the local vascular network

for the development of more effective treatment and angiogenesis due to their production of vas-

strategies [16]. cular endothelial growth factor (VEGF) [52]. MO

actively interacts with CSC, providing a  basis

CSC and the tumor microenvironment for the induction or differentiation of immune

The tumor microenvironment consists of a va- cells that suppress tumor growth, including sup-

riety of non-malignant cells, including tumor- pressive macrophages (M2-type) or regulatory

associated macrophages (M1/M2), tumor- T cells (Tregs) [51, 52]. In addition, the popula-

infiltrating lymphocytes, including regulatory T tion of tumor- associated macrophages (TAMs)

cells (Tregs), dendritic cells (DC), natural killer increases the activity of transcription factors

cells (NK) and myeloid suppressor cells (MDSC). such as Sox, Oct-4 and Nanog, which support the

These cells interact with each other and with tu- CSC in a state of proliferation and self-renewal.

mor cells, organizing an immune response, and MDSCs are a heterogeneous group of immature

can influence the behavior of other cells in the myeloid cells that play a role in immune response

tumor microenvironment either by direct regulation and tissue remodeling. It has been shown that

or with the help of produced mediators (cytokines, MDSCs have proangiogenic activity and induce

chemokines) interacting with receptors. These the production of metalloproteinases, which can

interactions can be mediated by both paracrine contribute to the formation of "metastatic" nich-

and autocrine pathways, as well as activation of es that facilitate the colonization of tissues by

co-inhibition or coactivation receptors. Cells are tumor cells. The tumor microenvironment induces

able to modulate the secretion of chemokines and differentiation of CD4+ T cells into various sub-

cytokines with an imbalance between those that populations of T cells, such as Tregs and T-17

perform suppressive and activating immune func- cells (Th17). The exact role of Th17 cells in tumor

tions. The source of intercellular communication immunity remains unclear, apparently depending

is a complex network of cytokines, chemokines, on the tumor stage and histological subtype. Inter-

growth factors, inflammatory mediators and en- estingly, recent reports suggest that Tregs, under

zymes. In general, the suppressive function of the certain conditions, express IL-17, which, together

immune system prevails in the tumor microenvi- with hypoxia, plays a crucial role in the regulation

ronment, and the process of its formation is called of cancer stem cells. However, the interactions

"tumor immunoredition" [50, 51]. between CSC and Treg, which significantly contrib-

Some studies have also shown that CSC can ute to the suppression of immunity in the tumor

activate mechanisms that allow tumors to avoid microenvironment, are still poorly understood.

attacks from immune cells, for example, loss of The location, type, density and functional sta-

cancer antigen expression and activation of on- tus of immune cells (T cells, B cells, NK cells, DC

cogenic pathways leading to the development cells, macrophages, neutrophils, monocytes and

64

Южно-Российский онкологический журнал 2024. Т. 5, № 4. С. 58-70

Харагезов Д. А., Антонян А. А., Златник Е. Ю., Сагакянц А. Б., Мирзоян Э. А., Айрапетова Т. Г., Лейман И. А., Милакин А. Г., Статешный О. Н., Иозефи К. Д.,

Хомидов М. А., Алексеев Э. А. Роль опухолевых стволовых клеток и иммунного микроокружения в патогенезе рака легкого: механизмы взаимодействия

и перспективы исследований

mast cells) in the immune microenvironment of After epigenetic reprogramming, M2 phenotype

a tumor characterize its heterogeneity. Using sin- macrophages are formed by differentiation and

gle-cell RNA sequencing technology, significant polarization, which can potentially contribute to

differences between the immune microenviron- the development of tumors [55]. Phenotypic M2

ment of adenocarcinoma and squamous cell lung supports tumor stem cell populations by secreting

cancer were confirmed [53]. This diversity affects chemokines and ligands that activate stem cell

the occurrence, growth of tumors, as well as the development pathways [57]. Enhanced methyla-

response to treatment. Therefore, many studies tion modifications and decreased chemokine ex-

have focused on studying the immune microenvi- pression in TAMs under hypoxic conditions alter

ronment of the tumor. Patients receiving neoad- the immune landscape in TME [57]. It was found

juvant chemotherapy had higher levels of PD-L1 that NEAT1 is highly expressed in lung cancer and

expression and T-cell subpopulations than those interacts with DNA methyltransferase DNMT1, reg-

who did not receive neoadjuvant chemotherapy for ulating the infiltration of lung cancer by cytotoxic

NSCLC [54]. In a study by Peng et al. [55] analysis T cells by inhibiting the cGAS/STING pathway [58].

of 26 types of immune cells in the immunological The proliferation, differentiation and survival of T

microenvironment of the tumor in 681 NSCLC sam- cells depend on the activity of EZH2 enhancers,

ples showed that patients with low levels of im- which are important epigenetic regulators of gene

mune cells and a predominance of macrophages expression. It is noteworthy that GSK126, an EZH2

in the tumor had a shorter recurrence-free survival. inhibitor, can stimulate the synthesis of Th1 chemo-

The total proportion and characteristics of T cells kines CXCL9 and CXCL10 in tumors and enhance

in a tumor are the main factors determining the their infiltration by CD8+ T cells [59]. The pres-

development of tumor progression. Depletion of ence of tumor- infiltrating B lymphocytes can be

T cells occurs immediately after oncogene initi- observed at all stages of lung cancer development,

ation and is the cause of patients' insensitivity and it has been found that histone modification

to anti- PD-1/PD-L1 therapy. During the depletion can also increase B cell infiltration [56]. Epigenetic

of T cells, inhibitory receptors such as CTLA-4, suppression of NKG2DL in SCLC leads to the ab-

TIM-3, LAG-3 and PD-1 are usually overexpressed sence of stimulating signals for activation of NK

on T cells, and effector cytokines such as IFN-γ cells, thereby increasing the aggressiveness and

decrease [55]. metastasis of SCLC [60].

It is known that the immune microenvironment of These studies show that the tumor microenvi-

a tumor can be altered by epigenetic immune edit- ronment plays an important role in the progression

ing. Epigenetic changes can be caused by inflam- of lung cancer. In particular, the condition of lung

mation [56]. The hypoxia- adapted cellular phenotype cancer stem cells, which is influenced by epigen-

is maintained in the tumor microenvironment due etic and immune changes in the tumor microenvi-

to the synergistic effect of epigenetic factors and ronment, is an important cause of treatment resis-

hypoxia-i nduced transcription factors (HIF). Under tance and the development of cancer recurrence.

conditions of hypoxia, intensive DNA methylation Potential targets for antitumor effects may be not

and histone modification occur, which promotes only molecules present in tumor cells, but also the

tumor growth, increases invasiveness and supports tumor microenvironment, primarily immune and

the stemness of cancer cells [56]. cytokine.

Currently, tumor- associated macrophages (TAM)

are the most widely studied immunosuppressive CONCLUSION

cells [55]. TAMs are collected at the site of inju-

ry after identification of chemokines, cytokines, Understanding the biology of tumor stem cells

inflammatory mediators, pathogens, or damage- is one of the most important tasks in clinical on-

related molecular structures (damps). There are cology. Recent studies have shown that these cells

TAM phenotypes: M1 and M2. The M1 phenotype play a significant role in the development of solid

is characterized by antitumor activity and, as tumors, such as lung cancer, which is becoming

a rule, is represented by activated macrophages. more common.

65

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 58-70

Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N., Iozefi K. D.,

Homidov M. A., Alekseev E. A. The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms of interaction

and research prospects

The importance of tumor stem cells in lung can- microenvironment in the context of lung cancer

cer is manifested not only through their ability to in clinical practice opens up new prospects for

form tumors, but also through interaction with the improving treatment and prognosis of patients.

tumor microenvironment, which plays a critical role Understanding the molecular mechanisms that

in tumor development and its response to therapy. regulate the activity and functionality of these

The tumor microenvironment, consisting of immune cells, as well as their interaction with the microen-

cells, fibroblasts, vascular network and extracellular vironment, offers new opportunities for developing

matrix, creates conditions that support the growth treatments aimed at both suppressing the activity

and survival of tumor stem cells, and also contrib- of tumor stem cells and modifying the microenvi-

utes to the development of resistance to chemother- ronment to fight the tumor. Successful research in

apy and radiation therapy. this area may be the key to more effective control

The integration of knowledge about the behav- of lung tumors and improving the quality of life

ior of tumor stem cells and interaction with their of patients.

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Information about authors:

Dmitrii A. Kharagezov – Cand. Sci. (Med.), MD, Head of the Department of Thoracic Oncology, National Medical Research Centre for Oncology,

Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0003-0640-2994, SPIN: 5120-0561, AuthorID: 733789, ResearcherID: AAZ-3638-2021, Scopus Author ID: 56626499300

Artur A. Antonyan  – PhD student of the 1st year, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0001-6449-7026, ResearcherID: JWQ-0734-2024

Elena Yu. Zlatnik – Dr. Sci. (Med.), MD, Professor, Chief Researcher, Laboratory of Immunophenotyping of Tumors, National Medical Research Centre

for Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0002-1410-122X, SPIN: 4137-7410, AuthorID: 327457, ResearcherID: AAI-1311-2020, Scopus Author ID: 6603160432

Alexander B. Sagakyants – Cand. Sci. (Biol.), head of the Laboratory of Immunophenotyping of Tumors, National Medical Research Centre for

Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0003-0874-5261, SPIN: 7272-1408, AuthorID: 426904, ResearcherID: M-8378-2019, Scopus Author ID: 24329773900

Ellada A. Mirzoyan – Cand. Sci. (Med.), MD, oncologist, researcher at the Department of Thoracic Oncology, National Medical Research Centre for

Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0002-0328-9714, SPIN: 2506-8605, AuthorID: 1002948, ResearcherID: AAZ-2780-2021, Scopus Author ID: 57221118516

Tamara G. Ayrapetova – Cand. Sci. (Med.), MD, oncologist at the Department of Thoracic Oncology, National Medical Research Centre for Oncology,

Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0001-5287-5800, SPIN: 8121-4039, AuthorID: 794672

Igor A. Leyman – Cand. Sci. (Med.), MD, oncologist at the Department of Thoracic Oncology, National Medical Research Centre for Oncology,

Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0003-2572-1624, SPIN: 2551-0999, AuthorID: 735699

Anton G. Milakin – MD, oncologist at the Department of Thoracic Oncology, National Medical Research Centre for Oncology, Rostov-on-Don,

Russian Federation

ORCID: https://orcid.org/0000-0002-2589-7606, SPIN: 7737-4737, AuthorID: 794734, Scopus Author ID: 57192109933

Oleg N. Stateshny – MD, oncologist at the Department of Thoracic Oncology, National Medical Research Centre for Oncology, Rostov-on-Don,

Russian Federation

ORCID: https://orcid.org/0000-0003-4513-7548, SPIN: 9917-1975, AuthorID: 1067071

Kristian D. Iozefi – MD, thoracic surgeon at the Department of Thoracic Oncology, National Medical Research Centre for Oncology, Rostov-on-Don,

Russian Federation

ORCID: https://orcid.org/0000-0002-5351-3251, SPIN: 1232-3097, AuthorID: 1122592, ResearcherID: AAZ-3632-2021

69

South Russian Journal of Cancer 2024. Vol. 5, No. 4. P. 58-70

Kharagezov D. A., Antonyan A. A., Zlatnik E. Yu., Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N., Iozefi K. D.,

Homidov M. A., Alekseev E. A. The role of tumor stem cells and the immune microenvironment in the pathogenesis of lung cancer: mechanisms of interaction

and research prospects

Mekhrullokhodzha A. Homidov – PhD student, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0003-0645-0937, SPIN: 1950-8737, AuthorID: 1067071, ResearcherID: JFK-3888-2023

Eduard K. Alekseev – MD, resident doctor, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0009-0007-4982-5491, ResearcherID: JWP-6340-2024

Contribution of the authors:

Kharagezov D. A., Zlatnik E. Yu. – scientific management;

Antonyan A. A. – writing the draft; material processing;

Sagakyants A. B., Mirzoyan E. A., Ayrapetova T. G., Leyman I. A., Milakin A. G., Stateshny O. N. Iozefi K. D., Homidov M. A., Alekseev E. K. – data

collection, analysis, technical editing, bibliography design.

70