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Role of Cytokines in Cancer

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Dear Colleagues,

In the past two decades, there has been an expansion in the understanding of the role of chronic inflammation in tumorigenesis. Infiltrating inflammatory cells in the tumor microenvironment secrete a wide array of cytokines, which play a critical role in various aspects of carcinogenesis. Cytokines, upon binding with their specific receptors on the immune and tumor cells, trigger oncogenic signaling pathways, which impact various aspects of cancer progression and metastasis. An in-depth understanding of these pathways offers avenues for multiple clinical applications, varying from diagnostics to drug discovery. Advances in technologies such as next-generation sequencing, CyTOF and liquid biopsy offer an enhanced understanding of the tumor microenvironment. In this Special Issue, entitled "Role of Cytokines in Cancer", authors are invited to contribute original research papers or review that provide critical insights into the role of cytokines in molecular events leading to the development and progression of cancer.

Dr. Venkataswarup Tiriveedhi
Guest Editor

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Published Papers (2 papers)

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22 pages, 3673 KiB

Open AccessArticle

Correlation of Immunomodulatory Cytokines with Tumor Volume and Cerebrospinal Fluid in Vestibular Schwannoma Patients

by Anna-Louisa Becker, Leila Scholle, Clara Helene Klause, Martin Sebastian Staege, Christian Strauss, Markus Otto, Stefan Rampp, Christian Scheller and Sandra Leisz

Cancers 2024, 16(17), 3002; https://doi.org/10.3390/cancers16173002 - 29 Aug 2024

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Abstract

Sporadic vestibular schwannomas (VSs) often exhibit slow or negligible growth. Nevertheless, some VSs increase significantly in volume within a few months or grow continuously. Recent evidence indicates a role of inflammation in promoting VS growth. Therefore, our study aimed to identify cytokines, which are associated with larger VSs. The expression of different cytokines in VS tumor samples and VS primary cultures was investigated. Additionally, the concentration of cytokines in cell culture supernatants of VS primary cultures and cerebrospinal fluid (CSF) of VS patients and healthy controls were determined. Correlation analysis of cytokine levels with tumor volume, growth rate, Koos grade, age, and hearing was examined with Spearman’s-rank test. The mRNA expression of CC-chemokine ligand (CCL) 18, growth differentiation factor (GDF) 15, and interferon regulatory factor 4 correlated positively with tumor volume. Moreover, the amount of GDF15 in the cell culture supernatant of primary cells correlated positively with tumor volume. The concentrations of the cytokines CCL2, CCL5, and CCL18 and transforming growth factor beta (TGFB) 1 in the CSF of the patients were significantly different from those in the CSF controls. Inhibition of immune cell infiltration could be a putative approach to prevent and control VS growth. Full article

(This article belongs to the Special Issue Role of Cytokines in Cancer)

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Figure 1

Figure 1
Workflow of the study. Of the 232 patients in the database, not all bio-material was available from each patient. In 176 patients, at least mRNA, primary culture, or CSF was present. mRNA analysis was obtained for 144 tumor samples, correlation with tumor volume could be obtained in 124 samples, and correlation with growth rate was found in 31 tumor samples. Quantification of cytokines in cell culture supernatants (CCSs) of primary cultures was performed in 45 samples, correlation with tumor volume was possible in 40 samples, and correlation with growth rate was possible in 12 samples. Concentration analysis of cytokines in CSF was feasible in 52 samples, whereby a correlation with tumor volume in 49 samples and a correlation with growth rate in 12 samples was obtained. Abbreviations: CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; NF2, NF2-related schwannomatosis; qPCR, quantitative real time polymerase chain reaction; VS, vestibular schwannoma. Full article ">Figure 2
Correlation analysis of the indicated markers and clinical parameters in 144 VS tumor samples using Spearman’s rank test. Depicted is the correlation between the mRNA levels of the 10 examined markers and age as well as Koos grade of 144 patients, and the correlation of marker levels with hearing class in 143 patients and with tumor volume in 124 patients. The correlation coefficient r is shown. Significant negative correlations (p < 0.05) are plotted in red and significant positive correlations (p < 0.05) in blue. Non-significant correlations are plotted uncolored. p-values of correlations were FDR-corrected for multiple comparisons. Full article ">Figure 3
Box-plots of the studied markers in 20 small and 20 large VSs. The box represents the values from the first to the third quartile. The whiskers from the box extend to 1.5 times the interquartile range. p-values from non-parametric Wilcoxon signed-rank test are presented. Full article ">Figure 4
The transcripts per million (TPM) of the indicated genes in 10 tumor samples and the 10 corresponding samples of vestibular nerves are shown. The TPM of the tumor is connected to the TPM of the corresponding nerve from the same patient by a line. The mRNA in the tumors was compared with the mRNA in the nerves using a Wilcoxon matched-paired signed rank test. The corresponding p-values are presented. Full article ">Figure 5
Concentrations of the investigated cytokines in the CCS of 45 primary cultures from patients with sporadic VSs. The borders of the box range from the 25th to 75th percentiles, and outliers are visualized as dots. The median is represented by the crossbar. Full article ">Figure 6
Correlation analysis of primary culture mRNA levels (with suffix qPCR) and concentration (with suffix ELISA) of various cytokines. Illustrated is the correlation of the mRNA levels and concentration of the investigated markers with one another, with age, hearing class, and Koos grade in 45 patients and with tumor volume in 44 patients. The correlation coefficient r is displayed in each panel. Areas plotted blue (p < 0.05) indicate significant positive correlations. Non-significant correlations are plotted uncolored. p-values of correlations were FDR-corrected for multiple comparisons. Full article ">Figure 7
The concentration of the cytokines CCL2, CCL5, CCL18, GDF15, and TGFB1 in the CSF of a control group (n = 14) was compared with the concentration in the CSF of 52 patients, as well as with the concentration in the CSF of the 20 largest and 20 smallest VSs. A Wilcoxon signed-rank test was performed to compare the groups. The median concentration is marked by the crossbar. The boundaries of the boxes represent the interquartile range, and the whiskers represent 1.5 times the interquartile range. Outliers are presented as dots. p-values of correlations were FDR-corrected for multiple comparisons. Full article ">Figure 8
Illustrated is the correlation of the concentration of CCL2, CCL5, CCL18, TGFB1, and GDF15 in the CSF of 52 patients with clinical parameters, such as age, hearing class, Koos grade, and tumor volume, as well as the correlation of the concentration of the five cytokines in the CSF of 12 patients with growth rate and relative growth rate. Spearman’s r is plotted for each correlation. Significant positive correlations (p < 0.05) are colored blue, and significant negative correlations are colored red. Non-significant correlations are plotted colorless. p-values of correlations were FDR-corrected for multiple comparisons. Full article ">

Abstract

Previous data indicate that one cycle of treatment with radium-223 (²²³Ra) did not significantly impair lymphocyte function in patients with metastasized, castration-resistant prostate cancer. The aim of the current study was to assess in 21 patients whether six cycles of this therapy had an effect on lymphocyte proliferation and interferon-γ and interleukin (IL)-10 ELISpot results. Lymphocyte proliferation after stimulation with microbial antigens and the production of interferon-γ continuously decreased after six cycles of radionuclide therapy, reaching statistical significance (p < 0.05) at months 1, 2, 4, and/or 6 after therapy. One month after the last cycle of therapy, 67% of patients showed a decrease in tumor burden. The tumor burden correlated negatively with IL-10 secretion at baseline, e.g., after stimulation with tetanus antigen (p < 0.0001, r = −0.82). As determined by receiver operating characteristic (ROC) curve analysis, tetanus-specific IL-10 spots at baseline had the highest predictive value (p = 0.005) for tumor burden at month 6, with an area under the curve (AUC) of 0.90 (sensitivity 100%, specificity 78%). In conclusion, we observed an additive effect of treatment with ²²³Ra on immune function and found that IL-10 secretion at baseline predicted tumor burden at month 6 after treatment. Full article

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