Editorial

3 pages, 185 KiB

Open AccessEditorial

Implication of Interleukin Family in Cancer Pathogenesis and Treatment

by Manuela Gonzalez-Aparicio and Carlos Alfaro

Cancers 2021, 13(5), 1016; https://doi.org/10.3390/cancers13051016 - 01 Mar 2021

Cited by 6 | Viewed by 1252

Cytokines are small proteins that are crucial for controlling the growth and activity of blood cells and other cells of the immune system [...] Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

Research

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20 pages, 2687 KiB

Open AccessArticle

Interleukin-18 and Hematopoietic Recovery after Allogeneic Stem Cell Transplantation

by Aleksandar Radujkovic, Lambros Kordelas, Rashit Bogdanov, Carsten Müller-Tidow, Dietrich W. Beelen, Peter Dreger and Thomas Luft

Cancers 2020, 12(10), 2789; https://doi.org/10.3390/cancers12102789 - 28 Sep 2020

Cited by 7 | Viewed by 2036

Abstract

Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate [...] Read more.

Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate the clinical impact of IL-18 status on hematopoietic function, the associations of pre-conditioning and day 0–3 cytokine levels with platelet and neutrophil recovery were analyzed in a training cohort of 714 allografted patients. In adjusted logistic regression analyses, both increasing pre-conditioning and day 0–3 IL-18 levels had a significantly higher adjusted odds ratio (aOR) of delayed platelet and neutrophil recovery on day +28 post-transplant (aOR per two-fold increase: 1.6–2.0). The adverse impact of high pre-conditioning IL-18 on day +28 platelet recovery was verified in an independent cohort of 673 allografted patients (aOR per two-fold increase: 1.8 and 1.7 for total and free IL-18, respectively). In both cohorts, a platelet count ≤20/nL on day +28 was associated with a significantly increased hazard of NRM (hazard ratio 2.13 and 2.94, respectively). Our findings support the hypothesis that elevated peritransplant IL-18 levels affect post-transplant HSPC function and may provide a rationale to explore modulation of IL-18 for improving alloSCT outcomes. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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17 pages, 1568 KiB

Open AccessArticle

Interleukin-6 and Lymphocyte Count Associated and Predicted the Progression of Frailty Syndrome in Prostate Cancer Patients Undergoing Antiandrogen Therapy

by Cristina Buigues, Rut Navarro-Martínez, Vanessa Sánchez-Martínez, María Serrano-Carrascosa, José Rubio-Briones and Omar Cauli

Cancers 2020, 12(7), 1716; https://doi.org/10.3390/cancers12071716 - 29 Jun 2020

Cited by 17 | Viewed by 2694

Abstract

Frailty syndrome is a functional state that includes a loss of ability to react to stressors, and is associated with poor outcomes, morbidity and premature mortality. The first line treatment in many men with prostate cancer (PCa) consists of an androgen-deprivation therapy (ADT) [...] Read more.

Frailty syndrome is a functional state that includes a loss of ability to react to stressors, and is associated with poor outcomes, morbidity and premature mortality. The first line treatment in many men with prostate cancer (PCa) consists of an androgen-deprivation therapy (ADT) which can promote or favor frailty syndrome and ADT may therefore favor the progression of frailty over time. Among the pathophysiological bases of frailty, the presence of chronic low-grade inflammation has been associated with its adverse outcomes, but longitudinal studies are needed to validate these biomarkers. In this study, we prospectively evaluate frailty syndrome and blood inflammatory markers (IL1-beta, IL-6, IL-8, TNF alpha, C reactive protein) and leukocytes were measured at baseline and an average of 1 year later in PCa under ADT. Frailty was defined as having three or more of the following components: low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed; prefrailty was defined as having one or two of those components. Multinomial regression analysis showed that among the inflammatory biomarkers, those significantly and repeatedly (baseline and follow-up time points) (p < 0.05) associated with frailty syndrome were high IL-6 levels and low lymphocyte counts in blood. Other biomarkers such as IL-8, monocyte counts and C reactive protein were significantly associated with frailty syndrome (p < 0.05) in cross-sectional analyses, but they do not predict frailty progression at 1 year-follow-up. Receiver operating characteristic curve analysis showed that both lymphocyte counts and IL-6 concentration significantly (p < 0.05) (although moderately) discriminate PCa patients that progressed in the severity of frailty syndrome. IL-6 and lymphocytes count are possible biomarkers, useful for identifying frail patients and predicting the progression of frailty in PCa under ADT. Our study suggests the use of these biomarkers to guide clinical decisions on prostate cancer treatment based on a multidisciplinary approach. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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34 pages, 5880 KiB

Open AccessArticle

Interleukins 4 and 13 and Their Receptors Are Differently Expressed in Gastrointestinal Tract Cancers, Depending on the Anatomical Site and Disease Advancement, and Improve Colon Cancer Cell Viability and Motility

by Iwona Bednarz-Misa, Dorota Diakowska, Izabela Szczuka, Paulina Fortuna, Agnieszka Kubiak, Joanna Rosińczuk and Małgorzata Krzystek-Korpacka

Cancers 2020, 12(6), 1463; https://doi.org/10.3390/cancers12061463 - 04 Jun 2020

Cited by 12 | Viewed by 3004

Abstract

Immunosuppressive interleukins (IL)-4 and 13 may directly promote cancer but neither their status nor role in gastrointestinal tract is clarified. We aim at quantifying ILs and their receptors in paired normal-tumor samples (n = 49/51) and sera (n = 263), using [...] Read more.

Immunosuppressive interleukins (IL)-4 and 13 may directly promote cancer but neither their status nor role in gastrointestinal tract is clarified. We aim at quantifying ILs and their receptors in paired normal-tumor samples (n = 49/51) and sera (n = 263), using immunoassays and RTqPCR, and screening for their effect on colonic cancer cells. Both ILs were elevated locally at protein level in all cancers but only IL13 transcripts in colon were upregulated. Interleukin and their receptor expression reflected cancer pathology to varying degrees, with the association frequently inverse and manifested in non-cancerous tissue. Positive correlation with cancer-promoting genes BCL2, BCLxL, HIF1A, VEGFA, ACTA2, CCL2, PTGS2, and CDKN1A, but not Ki67, was demonstrated, particularly for ILs’ receptors. Circulating IL-4 was elevated in all, while IL-13 only in colorectal or esophageal cancers, reflecting their advancement. IL4Ra and IL13Ra1 transcripts were downregulated by hypoxia and, in Caco-2, also by IL-4. Interleukin stimulation slightly improved colonic cancer cell viability, weakly upregulating BCL2 and Ki67 in HCT116 and HT-29. It affected cell motility more markedly and was consistently accompanied by upregulation of claudin-2. Gastrointestinal tract cancers are associated with IL-4 and IL-13 upregulation, which may facilitate cancer growth. Targeting both interleukins as an antineoplastic strategy warrants further investigation. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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11 pages, 790 KiB

Open AccessArticle

The Impact of IL-6 and IL-10 Gene Polymorphisms in Diffuse Large B-Cell Lymphoma Risk and Overall Survival in an Arab Population: A Case-Control Study

by Sohaib M. Al-Khatib, Nour Abdo, Laith N. AL-Eitan, Abdel-Hameed Al-Mistarehi, Deeb Jamil Zahran and Tariq Zuheir Kewan

Cancers 2020, 12(2), 382; https://doi.org/10.3390/cancers12020382 - 07 Feb 2020

Cited by 11 | Viewed by 2535

Abstract

B-cell lymphomas can be classified as Hodgkin and non-Hodgkin lymphomas. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin Lymphoma (NHL). The incidence of NHL is variable and affected by age, gender, racial, and geographic factors. There is strong evidence that the [...] Read more.

B-cell lymphomas can be classified as Hodgkin and non-Hodgkin lymphomas. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin Lymphoma (NHL). The incidence of NHL is variable and affected by age, gender, racial, and geographic factors. There is strong evidence that the immune-regulatory cytokines have a major role in hematologic malignancies. In this study, we analyzed the relationship between seven single nucleotide polymorphisms (SNPs) in two selected cytokines (IL-6 rs1800795G > C, rs1800796G > C, rs1800797G > A, IL-10 rs1800871G > A, rs1800872G > T, rs1800890A > T, rs1800896T > C) and the risk and overall survival of DLBCL patients in a Jordanian Arab population. One hundred and twenty-five DLBCL patients diagnosed at King Abdullah University Hospital (KAUH) from the period 2013–2018 and 238 matched healthy controls were included in the study. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissues. Genotyping of the genetic polymorphisms was conducted using a sequencing protocol. Our study showed no significant differences in the distribution of all studied polymorphisms of DLBCL between patients and controls. The IL-6 rs1800797 was the only SNP to show significant survival results, DLBCL subjects with the codominant model (GG/AG/AA) genotypes and recessive model (AA genotype in comparison with the combined GG/GA genotype) had worse overall survival (p = 0.028 and 0.016, respectively). Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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Review

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17 pages, 8969 KiB

Open AccessReview

Therapeutic Strategies for Targeting IL-1 in Cancer

by Adrian Gottschlich, Stefan Endres and Sebastian Kobold

Cancers 2021, 13(3), 477; https://doi.org/10.3390/cancers13030477 - 26 Jan 2021

Cited by 34 | Viewed by 4167

Abstract

Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several [...] Read more.

Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several clinical trials have been conducted, shedding light on the role of IL-1 blocking agents for the treatment of cancer. Additionally, recent developments in the field of immuno-oncology have implicated IL-1-induced signaling cascades as a major driver of severe chimeric antigen receptor T cell-associated toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity. In this review, we summarize current clinical trials investigating the role of IL-1 blockade in cancer treatment and elaborate the proposed mechanism of these innovative treatment approaches. Additionally, we highlight cutting-edge developments utilizing IL-1 blocking agents to enhance the safety and efficacy of adoptive T cell therapy. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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20 pages, 839 KiB

Open AccessReview

Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy

by Ying Yang and Andreas Lundqvist

Cancers 2020, 12(12), 3586; https://doi.org/10.3390/cancers12123586 - 30 Nov 2020

Cited by 71 | Viewed by 11556

Abstract

The type I cytokine family members interleukin-2 (IL-2) and IL-15 play important roles in the homeostasis of innate and adaptive immunity. Although IL-2 and IL-15 receptor complexes activate similar signal transduction cascades, triggering of these receptors results in different functional activities in lymphocytes. [...] Read more.

The type I cytokine family members interleukin-2 (IL-2) and IL-15 play important roles in the homeostasis of innate and adaptive immunity. Although IL-2 and IL-15 receptor complexes activate similar signal transduction cascades, triggering of these receptors results in different functional activities in lymphocytes. While IL-2 expands regulatory T cells and CD4+ helper T cells, IL-15 supports the development of central memory T cells and NK cells. Recent data have provided evidence that IL-2 and IL-15 differ in their ability to activate T and NK cells to resist various forms of immune suppression. The diverse roles of these two cytokines have on immune cells lead to critical therapeutic implications for cancer treatment. In this review, we discuss the distinct roles of IL-2 and IL-15 in activating various functions in T and NK cells with a particular focus on the signals that participate in the resistance of tumor-derived immune suppressive factors. Furthermore, we summarize current clinical applications of IL-2 and IL-15 in metastatic malignancies, either as monotherapy or in combination with other agents, and highlight the future trends for research on these cytokine-based immunotherapies. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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31 pages, 2598 KiB

Open AccessReview

Interleukin-1β and Cancer

by Cédric Rébé and François Ghiringhelli

Cancers 2020, 12(7), 1791; https://doi.org/10.3390/cancers12071791 - 04 Jul 2020

Cited by 134 | Viewed by 12411

Abstract

Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after “priming” of the cells and a second signal is required to allow IL-1β maturation by inflammasome-activated caspase-1. [...] Read more.

Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after “priming” of the cells and a second signal is required to allow IL-1β maturation by inflammasome-activated caspase-1. IL-1β is then released and leads to transcription of target genes through its ligation with IL-1R1 on target cells. IL-1β expression and maturation are guided by gene polymorphisms and by the cellular context. In cancer, IL-1β has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration, and metastasis. Moreover, anti-cancer treatments are able to promote IL-1β production by cancer or immune cells, with opposite effects on cancer progression. This raises the question of whether or not to use IL-1β inhibitors in cancer treatment. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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26 pages, 1163 KiB

Open AccessReview

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

by Alessandro Allegra, Caterina Musolino, Alessandro Tonacci, Giovanni Pioggia, Marco Casciaro and Sebastiano Gangemi

Cancers 2020, 12(2), 524; https://doi.org/10.3390/cancers12020524 - 24 Feb 2020

Cited by 20 | Viewed by 3698

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is the main cause of mortality among hematologic diseases in Western nations. B-CLL is correlated with an intense alteration of the immune system. The altered functions of innate immune elements and adaptive immune factors are interconnected in B-CLL [...] Read more.

B-cell chronic lymphocytic leukemia (B-CLL) is the main cause of mortality among hematologic diseases in Western nations. B-CLL is correlated with an intense alteration of the immune system. The altered functions of innate immune elements and adaptive immune factors are interconnected in B-CLL and are decisive for its onset, evolution, and therapeutic response. Modifications in the cytokine balance could support the growth of the leukemic clone via a modulation of cellular proliferation and apoptosis, as some cytokines have been reported to be able to affect the life of B-CLL cells in vivo. In this review, we will examine the role played by cytokines in the cellular dynamics of B-CLL patients, interpret the contradictions sometimes present in the literature regarding their action, and evaluate the possibility of manipulating their production in order to intervene in the natural history of the disease. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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12 pages, 909 KiB

Open AccessReview

Role of Interleukin-34 in Cancer

by Eleonora Franzè, Carmine Stolfi, Edoardo Troncone, Patrizio Scarozza and Giovanni Monteleone

Cancers 2020, 12(1), 252; https://doi.org/10.3390/cancers12010252 - 20 Jan 2020

Cited by 32 | Viewed by 4998

Abstract

Cross-talk between cancer cells and the immune cells occurring in the tumor microenvironment is crucial in promoting signals that foster tumor growth and metastasis. Both cancer cells and immune cells secrete various interleukins (IL), which, either directly or indirectly, stimulate cancer-cell proliferation, survival, [...] Read more.

Cross-talk between cancer cells and the immune cells occurring in the tumor microenvironment is crucial in promoting signals that foster tumor growth and metastasis. Both cancer cells and immune cells secrete various interleukins (IL), which, either directly or indirectly, stimulate cancer-cell proliferation, survival, and diffusion, as well as contribute to sculpt the immune microenvironment, thereby amplifying tumorigenic stimuli. IL-34, a cytokine produced by a wide range of cells, has been initially involved in the control of differentiation, proliferation, and survival of myeloid cells. More recent studies documented the overexpression of IL-34 in several cancers, such as hepatocarcinoma, osteosarcoma, multiple myeloma, colon cancer, and lung cancer, and showed that tumor cells can produce and functionally respond to this cytokine. In this review, we summarize the multiple roles of IL-34 in various cancers, with the aim to better understand the relationship between the expression of this cytokine and cancer behavior and to provide new insights for exploring a new potential therapeutic target. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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Other

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6 pages, 234 KiB

Open AccessCommentary

Relevant Cytokines in the B Cell Lymphoma Micro-Environment

by Günter Krause, Floyd Hassenrück and Michael Hallek

Cancers 2020, 12(9), 2525; https://doi.org/10.3390/cancers12092525 - 05 Sep 2020

Cited by 4 | Viewed by 3181

Abstract

Cytokines are soluble protein factors with importance in intercellular communication and, as such, play pivotal roles in the pathogenesis of B cell malignancies. Evidence from in vitro cultures permitted us to choose example cytokines that bind to different biochemical receptor types. Activated malignant [...] Read more.

Cytokines are soluble protein factors with importance in intercellular communication and, as such, play pivotal roles in the pathogenesis of B cell malignancies. Evidence from in vitro cultures permitted us to choose example cytokines that bind to different biochemical receptor types. Activated malignant B cells or stromal fibroblasts and macrophages prominently secrete the chemokines CCL3 or CXCL12 and CXCL13, respectively. Apart from helper T cells, various cell types of the B cell lymphoma microenvironment are capable of producing the cytokines IL-4, IL-6, IL-10 and TNFα. Owing to its impact on the development of myeloid cells, CSF-1 is among important soluble factors in the B cell lymphoma microenvironment. Inhibitors of B cell receptor-associated kinases often act via the blockade of cytokine production, but also prevent cytokine effects, e.g., chemotaxis. Increments in blood levels in chronic lymphocytic leukemia patients compared to healthy donors and normalization upon treatment with ibrutinib can be explained by producing cell types and modulation of cytokine production observed in vitro. Full article

(This article belongs to the Special Issue Interleukin in Cancer Pathogenesis and Treatment)

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