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Role of Cytokines and Their Receptors in Human Tumors and Immune-Regulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 8532

Special Issue Editor

Prof. Dr. Spaska Stanilova

E-Mail Website
Guest Editor
Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Armeiska 11 Street, Stara Zagora 6000, Bulgaria
Interests: gene polymorphism; colorectal cancer; cytokine; immune modulation

Special Issue Information

Dear Colleagues,

Cytokines are the main signaling molecules for the development of the immune response. After binding to their specific receptors on different types of immune cells, signal transduction pathways are activated, affecting the functional activity, proliferation, and differentiation of target cells. These processes concern both immune and tumor cells, as well as the development of tumor growth and metastasis. Further understanding of the induced cytokine signature in the tumor microenvironment will provide deeper insight into the molecular mechanisms of immune regulation during tumorigenesis. These new data can provide important information regarding the practical approach to the treatment of different tumor types.

This Special Issue will provide a platform for the newest scientific research concerning the molecular mechanisms of the regulation of cytokines and their receptors in immune cells in the tumor milieu. Original articles and reviews on signal transduction involving cytokines and their receptors, molecular genetics and epigenetics regulation, cell biology and immunology, and related fields, focusing on tumor development and metastasis, are welcome.

Prof. Dr. Spaska Stanilova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cytokines
  • cytokine receptors
  • immune regulation
  • cytokine expression regulation
  • tumorogenesis
  • tumor development

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Published Papers (4 papers)

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Research

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19 pages, 2194 KiB  
Article
TGF-β Induces the Secretion of Extracellular Vesicles Enriched with CD39 and CD73 from Cervical Cancer Cells
by Gabriela Molina-Castillo, Alberto Monroy-García, Rosario García-Rocha, Benny Weiss-Steider, Juan José Montesinos-Montesinos, Jorge Hernández-Montes, Christian Azucena Don-López, Marta Elena Castro-Manrreza, María Luisa Escobar-Sánchez and María de Lourdes Mora-García
Int. J. Mol. Sci. 2025, 26(6), 2413; https://doi.org/10.3390/ijms26062413 - 7 Mar 2025
Viewed by 631
Abstract
The presence of TGF-β in the tumor microenvironment of cervical cancer (CC) is important for tumor progression. In this study, we analyzed the effect of TGF-β on the expression of the ectonucleotidases CD39 and CD73, which are involved in the generation of adenosine [...] Read more.
The presence of TGF-β in the tumor microenvironment of cervical cancer (CC) is important for tumor progression. In this study, we analyzed the effect of TGF-β on the expression of the ectonucleotidases CD39 and CD73, which are involved in the generation of adenosine (Ado), in CC cells and in extracellular vesicles (EVs) secreted by these cells. Treatment of HeLa and CaSki cells for 72 h with recombinant human TGF-β increased the expression of CD39 and CD73 by 20 and 30% and by 40 and 100%, respectively. The addition of SB505124, an inhibitor of the TGF-β1 receptor, or GW4869, an inhibitor of exosome formation and release, reduced the expression and release of both ectonucleotidases in CC cells. Furthermore, TGF-β promoted the secretion of medium-large EVs (>130 nm) in HeLa cells (HeLa + TGF-β/EVs) and CaSki cells (CaSki + TGF-β/EVs), which increased the expression of CD39 (>20%) and CD73 (>60%), and EVs obtained from cells treated with TGF-β had a greater capacity to generate Ado than did EVs obtained from cells cultured in the absence of this factor (HeLa/EVs and CaSki/EVs). These findings suggest that the production of TGF-β in the CC TME can promote neoplastic progression through the secretion of EVs enriched with CD39 and CD73. Therefore, the inhibition of CD39+ CD73+ EVs could be a strategy for the treatment of CC. Full article
(This article belongs to the Special Issue Role of Cytokines and Their Receptors in Human Tumors and Immune-Regulation)
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16 pages, 3599 KiB  
Article
Artificial Tertiary Lymphoid Structures: Exploring Mesenchymal Stromal Cells as a Platform for Immune Niche Formation
by Ekaterina Zubkova, Alexander Kalinin, Irina Beloglazova, Ella Kurilina, Mikhail Menshikov, Yelena Parfyonova and Zoya Tsokolaeva
Int. J. Mol. Sci. 2024, 25(24), 13286; https://doi.org/10.3390/ijms252413286 - 11 Dec 2024
Viewed by 1423
Abstract
Constructing artificial tertiary lymphoid structures (TLSs) opens new avenues for advancing cancer immunotherapy and personalized medicine by creating controllable immune niches. Mesenchymal stromal cells (MSCs) offer an ideal stromal source for such constructs, given their potent immunomodulatory abilities and accessibility. In this study, [...] Read more.
Constructing artificial tertiary lymphoid structures (TLSs) opens new avenues for advancing cancer immunotherapy and personalized medicine by creating controllable immune niches. Mesenchymal stromal cells (MSCs) offer an ideal stromal source for such constructs, given their potent immunomodulatory abilities and accessibility. In this study, we explored the potential of adipose-derived MSCs to adopt TLS-supportive phenotypes and facilitate lymphocyte organization. Single-cell RNA sequencing revealed a distinct subpopulation of MSCs expressing key fibroblastic reticular cell (FRC)-associated markers, including IL-7, PDPN, and IL-15, though lacking follicular dendritic cell (FDC) markers. TNF-α stimulation, but not LTα2β1, further enhanced FRC marker expression (IL-7, PDPN, and ICAM1). Notably, in 3D spheroid co-culture with lymphocytes, MSCs upregulated additional FRC markers, specifically CCL21. Upon implantation into adipose tissue, MSC-lymphocyte organoids maintained structural integrity and showed extensive T-cell infiltration and partial vascularization after 15 days in vivo, although organized B-cell follicles and FDC markers were still lacking. These findings highlight MSCs’ intrinsic ability to adopt an FRC-like phenotype that supports T-cell and HEV organization, suggesting that further optimization, including genetic modification, may be needed to achieve an FDC phenotype and replicate the full architectural and functional complexity of TLSs. Full article
(This article belongs to the Special Issue Role of Cytokines and Their Receptors in Human Tumors and Immune-Regulation)
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19 pages, 2379 KiB  
Article
Deregulated Expression of IL-37 in Patients with Bladder Urothelial Cancer: The Diagnostic Potential of the IL-37e Isoform
by Maria Papasavva, Styliana Amvrosiou, Katerina-Marina Pilala, Konstantinos Soureas, Panayiota Christodoulou, Yuan Ji, Konstantinos Stravodimos, Damo Xu, Andreas Scorilas, Margaritis Avgeris and Maria-Ioanna Christodoulou
Int. J. Mol. Sci. 2023, 24(11), 9258; https://doi.org/10.3390/ijms24119258 - 25 May 2023
Cited by 4 | Viewed by 2497
Abstract
Cellular and molecular immune components play a crucial role in the development and perpetuation of human malignancies, shaping anti-tumor responses. A novel immune regulator is interleukin-37 (IL-37), already shown to be involved in the inflammation associated with the pathophysiology of many human disorders, [...] Read more.
Cellular and molecular immune components play a crucial role in the development and perpetuation of human malignancies, shaping anti-tumor responses. A novel immune regulator is interleukin-37 (IL-37), already shown to be involved in the inflammation associated with the pathophysiology of many human disorders, including cancer. The interplay between tumor and immune cells is of great importance, especially for highly immunogenic tumors such as bladder urothelial carcinoma (BLCA). This study aimed to investigate the potential of IL-37 and its receptor SIGIRR (single immunoglobulin IL-1-related receptor) to serve as prognostic and/or diagnostic markers in patients with BLCA. To this end, a series of bioinformatics tools processing -omics datasets and specifically designed qPCR assays on human BLCA tumors and cancer cell lines were utilized. Bioinformatics analysis revealed that IL-37 levels correlate with BLCA tumor development and are higher in patients with longer overall survival. Furthermore, mutations on SIGIRR are associated with enhanced infiltration of the tumor by regulatory T cells and dendritic cells. Based on the qPCR validation experiments, BLCA epithelial cells express the IL-37c and IL-37e isoforms, while the latter is the predominant variant detected in tumor biopsies, also associated with higher grade and the non-muscle-invasive type. This is the first time, to the best of our knowledge, that IL-37 and SIGIRR levels have been assessed in BLCA tumor lesions, and associations with pathological and survival parameters are described, while a transcript variant-specific signature is indicated to have a diagnostic potential. These data strongly indicate the need for further investigation of the involvement of this cytokine and interconnected molecules in the pathophysiology of the disease and its prospective as a therapeutic target and biomarker for BLCA. Full article
(This article belongs to the Special Issue Role of Cytokines and Their Receptors in Human Tumors and Immune-Regulation)
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Review

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17 pages, 1571 KiB  
Review
Navigating the Cytokine Seas: Targeting Cytokine Signaling Pathways in Cancer Therapy
by Noyko Stanilov, Tsvetelina Velikova and Spaska Stanilova
Int. J. Mol. Sci. 2024, 25(2), 1009; https://doi.org/10.3390/ijms25021009 - 13 Jan 2024
Cited by 6 | Viewed by 3235
Abstract
Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating continuous efforts to develop effective therapeutic strategies. Over the years, advancements in our understanding of the complex interplay between the immune system and cancer cells have led to the development [...] Read more.
Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating continuous efforts to develop effective therapeutic strategies. Over the years, advancements in our understanding of the complex interplay between the immune system and cancer cells have led to the development of immunotherapies that revolutionize cancer treatment. Cytokines, as key regulators of the immune response, are involved in both the initiation and progression of cancer by affecting inflammation and manipulating multiple intracellular signaling pathways that regulate cell growth, proliferation, and migration. Cytokines, as key regulators of inflammation, have emerged as promising candidates for cancer therapy. This review article aims to provide an overview of the significance of cytokines in cancer development and therapy by highlighting the importance of targeting cytokine signaling pathways as a potential therapeutic approach. Full article
(This article belongs to the Special Issue Role of Cytokines and Their Receptors in Human Tumors and Immune-Regulation)
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