Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma

Moreno-Guerrero, Silvia Selene; Ramírez-Pacheco, Arturo; Rocha-Ramirez, Luz María; Hernández-Pliego, Gabriela; Eguía-Aguilar, Pilar; Escobar-Sánchez, María Argelia; Reyes‐López, Alfonso; Juárez-Villegas, Luis Enrique; Sienra-Monge, Juan José Luis

doi:10.3390/cancers13030529

Cited by 11 publications

(5 citation statements)

References 67 publications

(46 reference statements)

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“…Like IL-6, serum levels of IL-8 are elevated in patients with high-risk NB tumors. 56 The role of MCP-1 in the TME of cancer including NB is however more complex including pro and anti-tumor activities. Tumor-derived MCP-1 elicits T cell chemotaxis, 57 and NB-derived MCP-1 is downregulated by MYCN and promotes the migration of iNKT cells thus contributing to tumor infiltration with immune cells.…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

et al. 2022

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Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF) and their precursor mesenchymal stromal cells (MSC) are often detected together in tumors, but how they cooperate is not well understood. Here, we show that TAM and CAF are the most abundant nonmalignant cells and are present together in untreated human neuroblastoma (NB) tumors that are also poorly infiltrated with T and natural killer (NK) cells. We then show that MSC and CAF-MSC harvested from NB tumors protected human monocytes (MN) from spontaneous apoptosis in an interleukin (IL)-6 dependent mechanism. The interactions of MN and MSC with NB cells resulted in a significant induction or increase in the expression of several pro-tumorigenic cytokines/chemokines (TGF-β1, MCP-1, IL-6, IL-8, and IL-4) but not of anti-tumorigenic cytokines (TNF-α, IL-12) by MN or MSC, while also inducing cytokine expression in quiescent NB cells. We then identified a TGF-β1/IL-6 pathway where TGF-β1 stimulated the expression of IL-6 in NB cells and MSC, promoting TAM survival. Evidence for the contribution of TAM and MSC to the activation of this pathway was then provided in xenotransplanted NB tumors and patients with primary tumors by demonstrating a direct correlation between the presence of CAF and p-SMAD2 and p-STAT3. The data highlight a new mechanism of interaction between TAM and CAF supporting their pro-tumorigenic function in cancer.

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Section: Discussionmentioning

confidence: 99%

Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

et al. 2022

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“…45,46 IL-6, however, is associated with poor survival when detected in NB patient blood and also promotes tumor progression due to modulation of the tumor microenvironment toward tolerance. 47,48 However, GD2-targeted immunotherapy in combination with IL-2 application revealed increased expression of serum IL-6 as well as IFN-gamma, IL-10, IL-18, and CCL2 and was associated with better outcome in patients with a lower serum level of Treg. 12 In summary, these findings support our results of increased Th1 (IFN-gamma, TNF-alpha) and Th2 (IL-4, IL-6, IL-10) cytokine levels in NB upon Treg depletion and therefore can be understood as an abrogation of Treg-mediated effector cell inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…There is little known regarding the function of IL‐4 in NB except that it helps to mature bone marrow‐derived immune/dendritic cells used in vitro for adoptive cell and vaccination treatment approaches in murine NB models 45,46 . IL‐6, however, is associated with poor survival when detected in NB patient blood and also promotes tumor progression due to modulation of the tumor microenvironment toward tolerance 47,48 . However, GD2‐targeted immunotherapy in combination with IL‐2 application revealed increased expression of serum IL‐6 as well as IFN‐gamma, IL‐10, IL‐18, and CCL2 and was associated with better outcome in patients with a lower serum level of Treg 12 .…”

Section: Discussionmentioning

confidence: 99%

Depletion of Foxp3+ regulatory T cells but not the absence of CD19+IL‐10+ regulatory B cells hinders tumor growth in a para‐orthotopic neuroblastoma mouse model

Weißenborn

Lenthe

Hinz

et al. 2022

Intl Journal of Cancer

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Adaptive immune cells with regulatory function reportedly mediate immune escape in a variety of tumors. Little is known regarding the relevance of the most prominent regulatory cell populations, namely Foxp3+ T regulatory cells (Tregs) and CD19+IL‐10+ B regulatory cells (Bregs), for neuroblastoma (NB) survival. After establishing a novel immunocompetent syngeneic NB mouse model where orthotopic tumors can be generated after intrarenal injection of NB975A cells, we studied the importance of Tregs and Bregs in Foxp3‐DTR mice whose Tregs can be depleted by diphtheria toxin (DT) application as well as in CD19‐specific IL‐10 deficient mice that lack IL‐10+ Bregs (CD19cre+/− × IL‐10fl/fl mice). We observed Foxp3 Treg cells in tumors from wild type mice. On the contrary, Bregs or B cells were scarce. Specific depletion of Tregs in Foxp3‐DTR mice resulted in an 85% reduction of tumor volume and weight compared to DT‐treated wild type mice and untreated Foxp3‐DTR mice. In contrast, NB tumor growth was not affected in CD19‐specific IL‐10 deficient mice. Similarly, mice lacking mature B cells (μMT mice) and CD19 deficient mice (CD19cre mice) showed no change in growth pattern of NB tumors. In Treg‐depleted mice, reduced tumor growth was associated with an increased concentration of IFN‐gamma, TNF‐alpha, IL‐4, IL‐6, and IL‐10 in isolated splenocytes. In summary, transient ablation of Tregs but not absence of Bregs hindered the growth of NB, strongly suggesting the therapeutic potential of targeting Tregs for this aggressive childhood tumor.

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“…However, such a contradiction between solid and hematological malignancies needs further studies on the action mechanism of IL-8 in these cancer types as it is known to play a critical role in epithelial-mesenchymal transition for migration and metastasis of cancer cells in solid cancers [76], apart from the observed variations due to the ethnicity of the subjects under study. In patients (Mexican children) with neuroblastoma, the homozygous AA genotype of rs4073 IL-8 appeared more frequently along with a high serum levels IL-8, which were associated with lower overall survival and the finding was further confirmed on the basis of an adverse prognosis in a multivariate model [77]. The pro-inflammatory cytokine TNF-α has originally been linked to necrosis in chemically induced sarcomas in mice and later with an ability to cause apoptosis of tumor cells through TNFR1 [78,79].…”

Section: Discussionmentioning

confidence: 70%

Molecular Evaluation of the Impact of Polymorphic Variants in Apoptotic (Bcl-2/Bax) and Proinflammatory Cytokine (TNF-α/IL-8) Genes on the Susceptibility and Progression of Myeloproliferative Neoplasms: A Case-Control Biomarker Study

Moawadh

Mir

Tayeb

et al. 2023

CIMB

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The regulation of apoptosis (the programmed cell death) is dependent on the crucial involvement of BCL2 and BAX. The Bax-248G>A and Bcl-2-938 C>A polymorphic variations in the promoter sequences of the Bax and Bcl-2 gene have been recently associated with low Bax expression, progression to advanced stages, treatment resistance, and shortened overall survival rate in some hematological malignancies, including chronic myeloid leukemia (CML) and other myeloproliferative neoplasms. Chronic inflammation has been linked to various stages of carcinogenesis wherein pro-inflammatory cytokines play diverse roles in influencing cancer microenvironment leading to cell invasion and cancer progression. Cytokines such as TNF-α and IL-8 have been implicated in cancer growth in both solid and hematological malignancies with studies showing their elevated levels in patients. Genomic approaches have in recent years provided significant knowledge with the regard to the association of certain SNPs (single nucleotide polymerphisms) either in a gene or its promoter that can influence its expression, with the risk and susceptibility to human diseases including cancer. This study has investigated the consequences of promoter SNPs in apoptosis genes Bax-248G>A (rs4645878)/Bcl-2-938C>A (rs2279115) and pro-inflammatory cytokines TNF-α rs1800629 G>A/IL-8 rs4073 T>A on the risk and susceptibility towards hematological cancers. The study design has 235 individuals both male and female enrolled as subjects that had 113 cases of MPDs (myeloproliferative disorders) and 122 healthy individuals as controls. The genotyping studies were conducted through ARMS PCR (amplification-refractory mutation system PCR). The Bcl-2-938 C>A polymorphism showed up in 22% of patients in the study, while it was observed in only 10% of normal controls. This difference in genotype and allele frequency between the two groups was significant (p = 0.025). Similarly, the Bax-248G>A polymorphism was detected in 6.48% of the patients and 4.54% of the normal controls, with a significant difference in genotype and allele frequency between the groups (p = 0.048). The results suggest that the Bcl-2-938 C>A variant is linked to an elevated risk of MPDs in the codominant, dominant, and recessive inheritance models. Moreover, the study indicated allele A as risk allele which can significantly increase the risk of MPDs unlike the C allele. In case of Bax gene covariants, these were associated with an increased risk of MPDs in the codominant inheritance model and dominant inheritance model. It was found that the allele A significantly enhanced the risk of MPDs unlike the G allele. The frequencies of IL-8 rs4073 T>A in patients was found to be TT (16.39%), AT (36.88%) and AA (46.72%), compared to controls who were more likely to have frequencies of TT (39.34%), AT (37.70%) and AA (22.95%) as such, respectively. There was a notable overrepresentation of the AA genotype and GG homozygotes among patients compared to controls in TNF-α polymorphic variants, with 6.55% of patients having the AA genotype and 84% of patients being GG homozygotes, compared to 1.63% and 69%, respectively in controls. The data from the current study provide partial but important evidence that polymorphisms in apoptotic genes Bcl-2-938C>A and Bax-248G>A and pro-inflammatory cytokines IL-8 rs4073 T>A and TNF-α G>A may help predict the clinical outcomes of patients and determine the significance of such polymorphic variations in the risk of myeloproliferative diseases and their role as prognostic markers in disease management using a case-control study approach.

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Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma

Cited by 11 publications

References 67 publications

Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

Depletion of Foxp3+ regulatory T cells but not the absence of CD19+IL‐10+ regulatory B cells hinders tumor growth in a para‐orthotopic neuroblastoma mouse model

Molecular Evaluation of the Impact of Polymorphic Variants in Apoptotic (Bcl-2/Bax) and Proinflammatory Cytokine (TNF-α/IL-8) Genes on the Susceptibility and Progression of Myeloproliferative Neoplasms: A Case-Control Biomarker Study

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