Cells

2024

Jump to: 2023, 2022

22 pages, 3889 KiB

Open AccessArticle

TLR9 Monotherapy in Immune-Competent Mice Suppresses Orthotopic Prostate Tumor Development

by Mark A. Miles, Raymond Luong, Eunice E. To, Jonathan R. Erlich, Stella Liong, Felicia Liong, Jessica M. Logan, John O’Leary, Doug A. Brooks and Stavros Selemidis

Cells 2024, 13(1), 97; https://doi.org/10.3390/cells13010097 - 2 Jan 2024

Cited by 1 | Viewed by 1972

Abstract

Prostate cancer is ranked second in the world for cancer-related deaths in men, highlighting the lack of effective therapies for advanced-stage disease. Toll-like receptors (TLRs) and immunity have a direct role in prostate cancer pathogenesis, but TLR9 has been reported to contribute to [...] Read more.

Prostate cancer is ranked second in the world for cancer-related deaths in men, highlighting the lack of effective therapies for advanced-stage disease. Toll-like receptors (TLRs) and immunity have a direct role in prostate cancer pathogenesis, but TLR9 has been reported to contribute to both the progression and inhibition of prostate tumorigenesis. To further understand this apparent disparity, we have investigated the effect of TLR9 stimulation on prostate cancer progression in an immune-competent, syngeneic orthotopic mouse model of prostate cancer. Here, we utilized the class B synthetic agonist CPG-1668 to provoke a TLR9-mediated systemic immune response and demonstrate a significant impairment of prostate tumorigenesis. Untreated tumors contained a high abundance of immune-cell infiltrates. However, pharmacological activation of TLR9 resulted in smaller tumors containing significantly fewer M1 macrophages and T cells. TLR9 stimulation of tumor cells in vitro had no effect on cell viability or its downstream transcriptional targets, whereas stimulation in macrophages suppressed cancer cell growth via type I IFN. This suggests that the antitumorigenic effects of CPG-1668 were predominantly mediated by an antitumor immune response. This study demonstrated that systemic TLR9 stimulation negatively regulates prostate cancer tumorigenesis and highlights TLR9 agonists as a useful therapeutic for the treatment of prostate cancer. Full article

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2023

Jump to: 2024, 2022

17 pages, 1233 KiB

Open AccessArticle

Molecular Effect of Variants in Toll-like Receptor 4 Gene in Saudi Patients with Type 2 Diabetes Mellitus

by Zeina S. Alkudmani, Amal F. Alshammary and Imran Ali Khan

Cells 2023, 12(19), 2340; https://doi.org/10.3390/cells12192340 - 23 Sep 2023

Cited by 6 | Viewed by 1530

Abstract

Single-nucleotide polymorphisms (SNPs) in the Toll-like receptor 4 (TLR4) gene have been documented in type 2 diabetes mellitus (T2DM) and other diseases in the Saudi population. We investigated the relationship between rs11536889, rs4986790, and rs4986791 SNPs in the TLR4 gene and [...] Read more.

Single-nucleotide polymorphisms (SNPs) in the Toll-like receptor 4 (TLR4) gene have been documented in type 2 diabetes mellitus (T2DM) and other diseases in the Saudi population. We investigated the relationship between rs11536889, rs4986790, and rs4986791 SNPs in the TLR4 gene and T2DM in the Saudi population; 105 patients with T2DM and 105 healthy controls were analyzed. The TLR4 gene was amplified through PCR, followed by restriction fragment length polymorphism analysis for rs4986791 and Sanger sequencing for rs11536889 and rs4986790 SNPs. The clinical and biochemical characteristics were associated with T2DM (p < 0.05). The rs11536889, rs4986790, and rs4986791 SNPs in control subjects followed the Hardy–Weinberg equilibrium (p > 0.05). Alleles were associated with rs11536889, rs4986791, heterozygous codominant, and dominant models (p < 0.05). However, the rs4986790 SNP was not associated with T2DM (p > 0.05). Logistic regression analysis showed that high-density lipoprotein cholesterol (HDLc) levels were associated with T2DM (p < 0.001). Analysis of variance showed that waist (p = 0.0005) and hip circumferences (p = 0.002) in rs4986790 and rs4986791 SNPs, in SBP (p = 0.001), DBP (p = 0.002), and HDLc levels (p = 0.003), were associated with T2DM subjects. T2DM was also associated with the haplotype (p < 0.001) but not with linkage disequilibrium. The gene–gene interaction was associated with the three SNPs studied in patients with T2DM according to the generalized multifactor dimensionality reduction model (p < 0.0001). Dendrogram and graphical depletion analysis revealed a moderate association in patients with T2DM. The results suggest that rs11536889 and rs4986790 SNPs are genotypically and allelically associated with T2DM in Saudi patients. Future functional studies are recommended to validate the genetic roles of these SNPs in the pathogenesis and progression of diseases. Full article

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18 pages, 2058 KiB

Open AccessArticle

Cognitive Alterations in Old Mice Are Associated with Intestinal Barrier Dysfunction and Induced Toll-like Receptor 2 and 4 Signaling in Different Brain Regions

by Annette Brandt, Franziska Kromm, Angélica Hernández-Arriaga, Inés Martínez Sánchez, Haktan Övül Bozkir, Raphaela Staltner, Anja Baumann, Amélia Camarinha-Silva, Rochellys Diaz Heijtz and Ina Bergheim

Cells 2023, 12(17), 2153; https://doi.org/10.3390/cells12172153 - 27 Aug 2023

Cited by 5 | Viewed by 2138

Abstract

Emerging evidence implicate the ‘microbiota–gut–brain axis’ in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like [...] Read more.

Emerging evidence implicate the ‘microbiota–gut–brain axis’ in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like receptor (TLR) 2 and TLR4, in blood and different brain regions, and depending signaling cascades are paralleling aging associated alterations of cognition in healthy aging mice. Cognitive function was assessed in the Y-maze and intestinal and brain tissue and blood were collected in young (4 months old) and old (24 months old) male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and TLR4 ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function, senescence and TLR2 and TLR4 signaling. Cognitive function was significantly impaired in old mice. Also, in old mice, intestinal microbiota composition was significantly altered, while the relative abundance of Gram-negative or Gram-positive bacteria in the small and large intestines at different ages was not altered. Moreover, intestinal barrier function was impaired in small intestine of old mice, and the levels of TLR2 and TLR4 ligands were also significantly higher in both portal and peripheral blood. Furthermore, levels of TLR2 and TLR4 ligands, and downstream markers of TLR signaling were higher in the hippocampal and prefrontal cortex of old mice compared to young animals. Taken together, our results suggest that even in ‘healthy’ aging, cognitive function is impaired in mice going along with an increased intestinal translocation of TLR ligands and alterations of TLR signaling in several brain regions. Full article

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27 pages, 6663 KiB

Open AccessArticle

Unraveling the Role of Toll-like Receptors in the Immunopathogenesis of Selected Primary and Secondary Immunodeficiencies

by Paulina Mertowska, Konrad Smolak, Sebastian Mertowski and Ewelina Grywalska

Cells 2023, 12(16), 2055; https://doi.org/10.3390/cells12162055 - 12 Aug 2023

Viewed by 1633

Abstract

The human immune system is a complex network of cells, tissues, and molecules that work together to defend the body against pathogens and maintain overall health. However, in some individuals, the immune system fails to function correctly, leading to immunodeficiencies. Immunodeficiencies can be [...] Read more.

The human immune system is a complex network of cells, tissues, and molecules that work together to defend the body against pathogens and maintain overall health. However, in some individuals, the immune system fails to function correctly, leading to immunodeficiencies. Immunodeficiencies can be classified into primary (PID) and secondary (SID) types, each with distinct underlying causes and manifestations. Toll-like receptors (TLRs), as key components of the immune system, have been implicated in the pathogenesis of both PID and SID. In this study, we aim to unravel the intricate involvement of TLR2, TLR4, TLR3, TLR7, TLR8, and TLR9 in the immunopathogenesis of common variable immunodeficiency—CVID (as PID)—and chronic lymphocytic leukemia—CLL (as SID). The obtained results indicate a significant increase in the percentage of all tested subpopulations of T lymphocytes and B lymphocytes showing positive expression of all analyzed TLRs in patients with CVID and CLL compared to healthy volunteers, constituting the control group, which is also confirmed by analysis of the concentration of soluble forms of these receptors in the plasma of patients. Furthermore, patients diagnosed with CVID are characterized by the percentage of all lymphocytes showing positive expression of the tested TLR2, TLR4, TLR3, and TLR9 and their plasma concentrations in relation to patients with CLL. By investigating the functions and interactions of TLRs within the immune system, we seek to shed light on their critical role in the development and progression of these immunodeficiencies. Through a comprehensive analysis of the literature and presented experimental data, we hope to deepen our understanding of the complex mechanisms by which TLRs contribute to the pathogenesis of PID and SID. Ultimately, our findings may provide valuable insights into developing targeted therapeutic strategies to mitigate the impact of these disorders on those affected by immunodeficiency. Full article

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19 pages, 4349 KiB

Open AccessArticle

TLR4 Overexpression Aggravates Bacterial Lipopolysaccharide-Induced Apoptosis via Excessive Autophagy and NF-κB/MAPK Signaling in Transgenic Mammal Models

by Sutian Wang, Kunli Zhang, Xuting Song, Qiuyan Huang, Sen Lin, Shoulong Deng, Meiyu Qi, Yecheng Yang, Qi Lu, Duowei Zhao, Fanming Meng, Jianhao Li, Zhengxing Lian, Chenglong Luo and Yuchang Yao

Cells 2023, 12(13), 1769; https://doi.org/10.3390/cells12131769 - 3 Jul 2023

Cited by 5 | Viewed by 2577

Abstract

Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy, and cell death, which have major impacts on the body’s physiological homeostasis. However, the role of TLR4 in bacterial [...] Read more.

Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy, and cell death, which have major impacts on the body’s physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals, which are closer to humans than rodents in many physiological characteristics, remains unknown. So far, few reports focus on the relationship between TLR, autophagy, and apoptosis in large mammal levels, and we urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in monocytes/macrophages of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in monocytes/macrophages of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced monocytes/macrophages apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress, and cell death. These findings also enrich the biological functions of TLR4 and provide powerful evidence for bacterial infection. Full article

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12 pages, 1276 KiB

Open AccessCommunication

Toll-like Receptor 4 Is Upregulated in Parkinson’s Disease Patients and Co-Localizes with pSer129αSyn: A Possible Link with the Pathology

by Carmela Conte, Angela Ingrassia, John Breve, John J. Bol, Evelien Timmermans-Huisman, Anne-Marie van Dam, Tommaso Beccari and Wilma D. J. van de Berg

Cells 2023, 12(10), 1368; https://doi.org/10.3390/cells12101368 - 11 May 2023

Cited by 10 | Viewed by 2454

Abstract

Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and [...] Read more.

Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in pyramidal neurons in the GTM of PD donors. Furthermore, we observed a co-localization of TLR4 and Iba-1 in glial cells of both SN and GTM. Our findings provide evidence for the increased expression of TLR4 in the PD brain and suggest that the interaction between TLR4 and pSer129-αSyn could play a role in mediating the neuroinflammatory response in PD. Full article

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13 pages, 5901 KiB

Open AccessReview

Synucleinopathies Take Their Toll: Are TLRs a Way to Go?

by Gabriella M. Mazzotta, Nadia Ceccato and Carmela Conte

Cells 2023, 12(9), 1231; https://doi.org/10.3390/cells12091231 - 24 Apr 2023

Cited by 9 | Viewed by 2015

Abstract

The misfolding and subsequent abnormal accumulation and aggregation of α-Synuclein (αSyn) as insoluble fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson’s disease (PD) and several neurodegenerative disorders. A combination of environmental and genetic factors is linked to αSyn [...] Read more.

The misfolding and subsequent abnormal accumulation and aggregation of α-Synuclein (αSyn) as insoluble fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson’s disease (PD) and several neurodegenerative disorders. A combination of environmental and genetic factors is linked to αSyn misfolding, among which neuroinflammation is recognized to play an important role. Indeed, a number of studies indicate that a Toll-like receptor (TLR)-mediated neuroinflammation might lead to a dopaminergic neural loss, suggesting that TLRs could participate in the pathogenesis of PD as promoters of immune/neuroinflammatory responses. Here we will summarize our current understanding on the mechanisms of αSyn aggregation and misfolding, focusing on the contribution of TLRs to the progression of α-synucleinopathies and speculating on their link with the non-motor disturbances associated with aging and neurodegenerative disorders. Full article

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2022

Jump to: 2024, 2023

16 pages, 1213 KiB

Open AccessReview

TLR9 and Glioma: Friends or Foes?

by Emna Fehri, Emna Ennaifer, Rahima Bel Haj Rhouma, Monia Ardhaoui and Samir Boubaker

Cells 2023, 12(1), 152; https://doi.org/10.3390/cells12010152 - 30 Dec 2022

Cited by 9 | Viewed by 4328

Abstract

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through [...] Read more.

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through specific transcription factors. Thus, it has been hypothesized that TLR9 may cause glioma. This article reviews the roles of TLR9 in the pathogenesis of glioma and its related signaling molecules in either defending or promoting glioma. TLR9 mediates the invasion-induced hypoxia of brain cancer cells by the activation of matrix metalloproteinases (2, 9, and 13) in brain tissues. In contrast, the combination of the TLR9 agonist CpG ODN to radiotherapy boosts the role of T cells in antitumor effects. The TLR9 agonist CpG ODN 107 also enhances the radiosensitivity of human glioma U87 cells by blocking tumor angiogenesis. CpG enhances apoptosis in vitro and in vivo. Furthermore, it can enhance the antigen-presenting capacity of microglia, switch immune response toward CD8 T cells, and reduce the number of CD4CD25 Treg cells. CpG ODN shows promise as a potent immunotherapeutic drug against cancer, but specific cautions should be taken when activating TLR9, especially in the case of glioblastoma. Full article

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15 pages, 1319 KiB

Open AccessArticle

The Toll-like Receptor 4 Polymorphism Asp299Gly Is Associated with an Increased Risk of Ovarian Cancer

by Katarzyna D. Kania, Daria Haręża, Jacek R. Wilczyński, Miłosz Wilczyński, Dariusz Jarych, Andrzej Malinowski and Edyta Paradowska

Cells 2022, 11(19), 3137; https://doi.org/10.3390/cells11193137 - 5 Oct 2022

Cited by 8 | Viewed by 2273

Abstract

Ovarian cancer (OC) is one of the most common cancers threatening women’s lives around the world. Epithelial ovarian tumors represent the most common ovarian neoplasms. Most OC patients are diagnosed at the advanced stage, and there is an urgent need to identify novel [...] Read more.

Ovarian cancer (OC) is one of the most common cancers threatening women’s lives around the world. Epithelial ovarian tumors represent the most common ovarian neoplasms. Most OC patients are diagnosed at the advanced stage, and there is an urgent need to identify novel biomarkers of the disease. Single-nucleotide polymorphisms (SNPs) in TLR genes may serve as crucial markers of cancer susceptibility. We investigated the frequency of TLR polymorphisms in a group of 200 women, including 70 with OC. Four SNPs, two each in TLR4 (rs4986790 and rs4986791) and TLR9 (rs187084 and rs5743836), were analyzed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The digested fragments were separated and identified by multicapillary electrophoresis. The load quantification of human papillomavirus (HPV) types 16/18 was determined using a digital droplet PCR method. We found an increased frequency of heterozygous genotype and minor allele of the TLR4 rs4986790 SNP in women with OC compared with healthy controls, and this result remained highly significant after Bonferroni’s correction for multiple testing (p < 0.0001). No evidence of linkage disequilibrium was found with any of the examined TLR SNPs. The findings suggest that the TLR4 Asp299Gly polymorphism could be a genetic risk factor for the development of OC. Full article

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14 pages, 4574 KiB

Open AccessArticle

Identification of Biomarkers Related to M2 Macrophage Infiltration in Alzheimer’s Disease

by Caixiu Lin, Congcong Xu, Yongji Zhou, Anqi Chen and Baiye Jin

Cells 2022, 11(15), 2365; https://doi.org/10.3390/cells11152365 - 1 Aug 2022

Cited by 9 | Viewed by 3037

Abstract

Many studies have demonstrated that neuroinflammation contributes to the onset and development of Alzheimer’s disease (AD). The infiltration of immune cells in the brain was observed in AD. The purpose of the present study was to verify potential mechanisms and screen out biomarkers [...] Read more.

Many studies have demonstrated that neuroinflammation contributes to the onset and development of Alzheimer’s disease (AD). The infiltration of immune cells in the brain was observed in AD. The purpose of the present study was to verify potential mechanisms and screen out biomarkers related to immune infiltration in AD. We collected the expression profiling datasets of AD patients and healthy donors from the NCBI’s Gene Expression Omnibus (GEO) database. We confirmed that immune-related mechanisms were involved in AD using differentially expressed genes analysis and functional enrichment analysis. We then found that M2 macrophage infiltration was most positively correlated with AD according to the CIBERSORT algorithm and a weighted gene co-expression network analysis (WGCNA). TLR2, FCGR2A, ITGB2, NCKAP1L and CYBA were identified as hub genes correlated with M2 macrophage infiltration in AD. Furthermore, the expression levels of these hub genes were positively correlated with Aβ42 and β-secretase activity. A diagnostic model of these hub genes was constructed, which showed a high area under the curve (AUC) value in both the derivation and validation cohorts. Overall, our work further expanded our understanding of the immunological mechanisms of AD and provided new insights into therapeutic strategies in AD. Full article

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31 pages, 4302 KiB

Open AccessArticle

Neuroinflammatory Gene Expression Analysis Reveals Pathways of Interest as Potential Targets to Improve the Recording Performance of Intracortical Microelectrodes

by Sydney Song, Brianna Regan, Evon S. Ereifej, E. Ricky Chan and Jeffrey R. Capadona

Cells 2022, 11(15), 2348; https://doi.org/10.3390/cells11152348 - 30 Jul 2022

Cited by 16 | Viewed by 2454

Abstract

Intracortical microelectrodes are a critical component of brain-machine interface (BMI) systems. The recording performance of intracortical microelectrodes used for both basic neuroscience research and clinical applications of BMIs decreases over time, limiting the utility of the devices. The neuroinflammatory response to the microelectrode [...] Read more.

Intracortical microelectrodes are a critical component of brain-machine interface (BMI) systems. The recording performance of intracortical microelectrodes used for both basic neuroscience research and clinical applications of BMIs decreases over time, limiting the utility of the devices. The neuroinflammatory response to the microelectrode has been identified as a significant contributing factor to its performance. Traditionally, pathological assessment has been limited to a dozen or so known neuroinflammatory proteins, and only a few groups have begun to explore changes in gene expression following microelectrode implantation. Our initial characterization of gene expression profiles of the neuroinflammatory response to mice implanted with non-functional intracortical probes revealed many upregulated genes that could inform future therapeutic targets. Emphasis was placed on the most significant gene expression changes and genes involved in multiple innate immune sets, including Cd14, C3, Itgam, and Irak4. In previous studies, inhibition of Cluster of Differentiation 14 (Cd14) improved microelectrode performance for up to two weeks after electrode implantation, suggesting CD14 can be explored as a potential therapeutic target. However, all measures of improvements in signal quality and electrode performance lost statistical significance after two weeks. Therefore, the current study investigated the expression of genes in the neuroinflammatory pathway at the tissue-microelectrode interface in Cd14^−/− mice to understand better how Cd14 inhibition was connected to temporary improvements in recording quality over the initial 2-weeks post-surgery, allowing for the identification of potential co-therapeutic targets that may work synergistically with or after CD14 inhibition to improve microelectrode performance. Full article

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12 pages, 1852 KiB

Open AccessFeature PaperArticle

A Therapeutic Whole-Tumor-Cell Vaccine Covalently Conjugated with a TLR7 Agonist

by Huju Chi, Yue Hao, Xia Wang, Li Tang, Yongqiang Deng, Xianxiong Chen, Feng Gao, Ou Sha and Guangyi Jin

Cells 2022, 11(13), 1986; https://doi.org/10.3390/cells11131986 - 21 Jun 2022

Cited by 9 | Viewed by 2712

Abstract

A single-protein or -peptide vaccine is not sufficient to arouse immune responses in cancer therapy. A whole-tumor-cell vaccine with complete cancer cell antigens and all conformations elicits robust immune responses and is a promising method for the treatment of advanced malignant tumors. In [...] Read more.

A single-protein or -peptide vaccine is not sufficient to arouse immune responses in cancer therapy. A whole-tumor-cell vaccine with complete cancer cell antigens and all conformations elicits robust immune responses and is a promising method for the treatment of advanced malignant tumors. In this study, we used 5-azacitidine to stimulate B16-F10 melanoma cells to express toll-like receptor (TLR) 3 on the cell surface and then chemically linked SZU-106, a small-molecule TLR7 agonist, to the cell surface with a pegylated linker to produce a novel whole-tumor-cell vaccine, abbreviated as Aza-BFcell-106. The vaccine stimulated mouse splenic lymphocytes and bone marrow-derived dendritic cells to secrete cytokines, promoted the maturation of dendritic cells and enhanced the capability of dendritic cells to present antigens. In a mouse model of melanoma, the vaccine effectively inhibited tumor growth, decreased tumor volume and prolonged survival. Further combination of the vaccine with a chemokine inhibitor, reparixin, significantly increased the infiltration of CD4+ and CD8+ T cells into the tumor environment, while the antitumor effect was significantly enhanced. The whole-tumor-cell vaccine Aza-BFcell-106 induced immune-activating responses in both in vitro and in vivo experiments, indicating that this vaccine has great potential to treat advanced malignant tumors. Full article

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