CXCL9

Gene Summary

Gene:CXCL9; C-X-C motif chemokine ligand 9
Aliases: CMK, MIG, Humig, SCYB9, crg-10
Location:4q21.1
Summary:This antimicrobial gene encodes a protein thought to be involved in T cell trafficking. The encoded protein binds to C-X-C motif chemokine 3 and is a chemoattractant for lymphocytes but not for neutrophils. [provided by RefSeq, Sep 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-X-C motif chemokine 9
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • TNF
  • Chemokine CXCL10
  • Gene Expression Profiling
  • Receptors, Cytokine
  • Up-Regulation
  • Melanoma
  • Intercellular Signaling Peptides and Proteins
  • CXCR3
  • Chemokines
  • Skin Cancer
  • STAT1 Transcription Factor
  • Chromosome 4
  • Breast Cancer
  • Chemokines, CXC
  • Th2 Cells
  • Lymphocytes, Tumor-Infiltrating
  • RTPCR
  • Interferon-gamma
  • Messenger RNA
  • Neoplasm Proteins
  • Cancer Gene Expression Regulation
  • Vaccination
  • Adolescents
  • Staging
  • T-Lymphocytes
  • Trans-Activators
  • Transcription Factors
  • Chemokine CXCL11
  • Protein Array Analysis
  • CD8-Positive T-Lymphocytes
  • Immunohistochemistry
  • Chronic Lymphocytic Leukemia
  • Chemokine CXCL9
  • Cytokines
  • Cell Proliferation
  • Gene Expression
  • Tandem Mass Spectrometry
  • Receptors, Chemokine
  • Cell Movement
  • Biomarkers, Tumor
  • Macrophages
  • B-Lymphocytes
  • Signal Transduction
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CXCL9 (cancer-related)

Yahata T, Mizoguchi M, Kimura A, et al.
Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cancer progression.
Cancer Sci. 2019; 110(4):1279-1292 [PubMed] Free Access to Full Article Related Publications
Programmed cell death ligand 1 (PD-L1) on tumor cells suppresses anti-tumor immunity and has an unfavorable prognostic impact in ovarian cancer patients. We herein report the pathophysiological and therapeutic impacts of PD-L1 disruption in ovarian cancer. PD-L1 was genetically disrupted in the murine ovarian cancer cell line ID8 using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome editing. PD-L1 knockout (KO) and control ovarian cancer cells were intraperitoneally inoculated into syngeneic mice, and survival and tumor dissemination were evaluated. Survival times were significantly longer in the PD-L1-KO ID8-inoculated groups than in their control groups, and its therapeutic benefit was enhanced in combination with the cisplatin treatment. Tumor weights and ascites volumes were significantly lower in the PD-L1-KO ID8 groups than in their control groups. Immunohistochemical and immunofluorescence analyses showed that intratumoral CD4

Qian L, Yu S, Yin C, et al.
Plasma IFN-γ-inducible chemokines CXCL9 and CXCL10 correlate with survival and chemotherapeutic efficacy in advanced pancreatic ductal adenocarcinoma.
Pancreatology. 2019; 19(2):340-345 [PubMed] Related Publications
OBJECTIVES: Recent studies have suggested that the CXCL9, 10, 11/CXCR3 axis is significant in immune regulation and therapeutic efficacy in human cancers; however, its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. This study serves to evaluate the prognostic prediction value of plasma IFN-γ-inducible chemokines, CXCL9 and CXCL10, in advanced PDAC.
METHODS: Two hundred patients with advanced PDAC receiving palliative chemotherapy were retrospectively recruited. The association between Plasma CXCL9/CXCL10 levels and survival time was first analyzed in a test group of 110 patients and then confirmed in a validation group of 90 patients.
RESULTS: High levels of CXCL9 and CXCL10 were significantly correlated with longer overall survival (OS) in advanced PDAC patients (314 vs. 136 days for CXCL9, P < 0.0001, and 374 vs. 163 days for CXCL10, P < 0.0001, respectively) in the test group, which was consistent with the results derived from the validation group. In addition, high levels of CXCL9 and CXCL10 were associated with longer time to progression (TTP) in patients receiving chemotherapy (100 vs. 60 days for CXCL9, P = 0.0021, and 104 vs. 67 days for CXCL10, P = 0.0057, respectively). Multivariate analyses confirmed that CXCL9 and CXCL10 were independent prognostic predictors for OS (hazard ratio [HR]: 0.452, P < 0.001 for CXCL9; and HR: 0.586, P = 0.007 for CXCL10, respectively) and TTP (HR: 0.656, P = 0.015 for CXCL9; and HR: 0.687, P = 0.040 for CXCL10, respectively).
CONCLUSIONS: Plasma CXCL9 and CXCL10 can be used to predict survival of advanced PDAC patients receiving chemotherapy, allowing clinicians to potentially improve treatment outcomes by identifying candidates for aggressive therapy.

De Silva P, Garaud S, Solinas C, et al.
FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer.
EBioMedicine. 2019; 39:226-238 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: FOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC).
METHODS: FOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1
FINDING: FOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1
INTERPRETATION: These data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression. FUND: Belgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux.

Alshareeda AT, Rakha E, Alghwainem A, et al.
The effect of human placental chorionic villi derived mesenchymal stem cell on triple-negative breast cancer hallmarks.
PLoS One. 2018; 13(11):e0207593 [PubMed] Free Access to Full Article Related Publications
Mesenchymal stem cells (MSCs) can influence the tumour microenvironment (TEM) and play a major role in tumourigenesis. Triple-negative [Ostrogen receptor (ER-), Progesterone receptor (PgR-), and HER2/neu receptor (HER2-)] breast cancer (TNBC) is an aggressive class of BC characterized by poor prognosis and lacks the benefit of routinely available targeted therapies. This study aims to investigate the effect of human placental chorionic villi derived MSCs (CVMSCs) on the behavior of TNBC in vitro. This was done by assaying different cancer hallmarks including proliferation, migration and angiogenesis. Cell proliferation rate of TNBC cell line (MDA-MB231) was monitored in real time using the xCELLigence system. Whereas, Boyden chamber migration assay was used to measure MDA-MB231 motility and invasiveness toward CVMSCs. Finally, a three-dimensional (3D) model using a co-culture system of CVMSCs with MDA-MB231 with or without the addition of human umbilical vein endothelial cells (HUVECs) was created to assess tumour angiogenesis in vitro. CVMSCs were able to significantly reduce the proliferative and migratory capacity of MDA-MB231 cells. Co-culturing of MDA-MB231 with CVMSCs, not only inhibited the tube formation ability of HUVECs but also reduced the expression of the BC characteristic cytokines; IL-10, IL-12, CXCL9 and CXCL10 of CVMSCs. These results support the hypothesis that CVMSCs can influence the behavior of TNBC cells and provides a basic for a potential therapeutic approach in a pre-clinical settings. The data from this study also highlight the complexity of the in vitro cancer angiogenesis model settings and regulations.

Braun SA, Baran J, Schrumpf H, et al.
Ingenol mebutate induces a tumor cell-directed inflammatory response and antimicrobial peptides thereby promoting rapid tumor destruction and wound healing.
Eur J Med Res. 2018; 23(1):45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations.
METHODS: The effects of IM (10
RESULTS: Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10
CONCLUSIONS: Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10

Xu M, Wang Y, He HT, Yang Q
MiR-589-5p is a potential prognostic marker of hepatocellular carcinoma and regulates tumor cell growth by targeting MIG-6.
Neoplasma. 2018; 65(5):753-761 [PubMed] Related Publications
MicroRNAs (miRNAs) are small noncoding RNAs approximately with 22 nucleotides. Accumulating evidence indicates that microRNAs are involved in carcinogenesis and tumor progression. Some recent investigations have also reported that several microRNAs could act as biomarkers in cancer diagnosis and prognosis. MicroRNA-589-5p (miR-589-5p) is a less studied microRNA, in this study, we explored its roles in hepatocellular carcinoma (HCC). We analyzed miR-589-5p expression in HCC tissues by sequencing data and proved the expression in liver cancer cell lines by quantitative real-time PCR (qRT-PCR). We studied the effect of miR-589-5p on the growth of liver cancer cells by MTT assay, colony formation and flow cytometry, and identified its target gene by luciferase reporter assay. We found that miR-589-5p was commonly overexpressed in HCC specimens. High expression of miR-589-5p was a risk factor for HCC patient (Hazard ratio [HR] = 1.434; 95% confidence intervals [CI] = 1.006-2.044; p = 0.046). We also found miR-589-5p had higher expression in hepatocarcinoma cell lines HepG2 and HuH-7 than did in normal hepatocyte Lo-2. We identified that suppression of miR-589-5p inhibited cell proliferation and cell cycle progression by loss-of-function studies. Furthermore, we found mitogen-inducible gene 6 (MIG-6) to be a target of miR-589-5p. Our study demonstrated that miR-589-5p facilitated the growth of liver cancer cells by targeting MIG-6 and could be a prognosis biomarker for HCC. Suppression of miR-589-5p may be a feasible approach for inhibiting HCC progress.

Ruiduo C, Ying D, Qiwei W
CXCL9 promotes the progression of diffuse large B-cell lymphoma through up-regulating β-catenin.
Biomed Pharmacother. 2018; 107:689-695 [PubMed] Related Publications
CXC chemokine ligand 9, a member of "cytokine milieu", makes up the microenvironment of lymphoma and plays an important role in the occurrence and development of lymphoma. However, the role of CXC chemokine ligand 9 and its underlying mechanism remains largely unknown in the progression of diffuse large B-cell lymphoma. Wnt/ β -catenin signaling is reported to play an important role in diffuse large B-cell lymphoma, and the overexpression and nuclear accentuation of β-catenin in diffuse large B-cell lymphoma patients' tissues were closely associated with the advanced clinical staging. The present study aimed to explore the effects of CXC chemokine ligand 9 on the progression of diffuse large B-cell lymphoma and determine if β -catenin is involved in this process. We firstly detected the expression pattern of CXC chemokine ligand 9 in diffuse large B-cell lymphoma tissues and cell lines, and determined the relationship between CXC chemokine ligand 9 expression level and patients' progression and prognosis. Then we used the loss/gain of function approach to determine the effects of CXC chemokine ligand 9 on cell viability, apoptosis and migration. Finally, we assessed the expression and subcellular location of β-catenin after CXC chemokine ligand 9 up/down-regulation by Western Blot. Our results showed that CXC chemokine ligand 9 was highly expressed in diffuse large B-cell lymphoma tissues and cell lines, which showed close association with patients' advanced clinical progression and shorter overall survival. Up-regulation of CXC chemokine ligand 9 promoted the viability and migration and repressed the apoptosis of OCI-Ly8 cells, as well as increased β-catenin expression and translocated it from cytoplasm to nuclear, while these effects were abolished when knockdown β-catenin. In conclusion, this work reveals that CXC chemokine ligand 9 promotes the progression of diffuse large B-cell lymphoma in a β-catenin-dependent manner. Our study provides evidence for the mechanism by which CXC chemokine ligand 9 may function as an oncogene and the potential of serving CXC chemokine ligand 9 as a therapeutic target for diffuse large B-cell lymphoma.

Qin Y, Vasilatos SN, Chen L, et al.
Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade.
Oncogene. 2019; 38(3):390-405 [PubMed] Free Access to Full Article Related Publications
Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype. In silico analysis of The Cancer Genome Atlas (TCGA) data shows that expression of histone lysine-specific demethylase 1 (LSD1) is inversely associated with the levels of cytotoxic T cell-attracting chemokines (C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 and 10 (CXCL9, CXCL10)) and programmed death-ligand 1 (PD-L1) in clinical TNBC specimens. Tiling chromatin immunoprecipitation study showed that re-expression of chemokines by LSD1 inhibition is associated with increased H3K4me2 levels at proximal promoter regions. Rescue experiments using concurrent treatment with small interfering RNA or inhibitor of chemokine receptors blocked LSD1 inhibitor-enhanced CD8+ T cell migration, indicating a critical role of key T cell chemokines in LSD1-mediated CD8+ lymphocyte trafficking to the tumor microenvironment. In mice bearing TNBC xenograft tumors, anti-PD-1 antibody alone failed to elicit obvious therapeutic effect. However, combining LSD1 inhibitors with PD-1 antibody significantly suppressed tumor growth and pulmonary metastasis, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in xenograft tumors. Overall, these results suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.

Yoo JY, Kang HB, Broaddus RR, et al.
MIG-6 suppresses endometrial epithelial cell proliferation by inhibiting phospho-AKT.
BMC Cancer. 2018; 18(1):605 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant hyperactivation of epithelial proliferation, AKT signaling, and association with unopposed estrogen (E2) exposure is the most common endometrial cancer dysfunction. In the normal uterus, progesterone (P4) inhibits proliferation by coordinating stromal-epithelial cross-talk, which we previously showed is mediated by the function of Mitogen-inducible gene 6 (Mig-6). Despite their attractive characteristics, non-surgical conservative therapies based on progesterone alone have not been universally successful. One barrier to this success has been the lack of understanding of the P4 effect on endometrial cells.
METHOD: To further understand the role of Mig-6 and P4 in controlling uterine proliferation, we developed a Sprr2f-cre driven mouse model where Mig-6 is specifically ablated only in the epithelial cells of the uterus (Sprr2f
RESULTS: Sprr2f
CONCLUSIONS: These data suggest that endometrial epithelial cell proliferation is regulated by P4 mediated Mig-6 inhibition of AKT phosphorylation, uncovering new mechanisms of P4 action. This information may help guide more effective non-surgical interventions in the future.

Ren K, Zhang J, Gu X, et al.
Migration-inducing gene-7 independently predicts poor prognosis of human osteosarcoma and is associated with vasculogenic mimicry.
Exp Cell Res. 2018; 369(1):80-89 [PubMed] Related Publications
Vasculogenic mimicry (VM) is a special type of vascular channel formed by tumor cells without endothelial cell participation. Migration-inducing gene 7 (MIG-7) plays an important role in regulating VM. In this study, immunohistochemical staining was used to detect MIG-7 in tissue specimens from 141 primary osteosarcoma patients, and the relationship between MIG-7 and VM was examined. Survival analysis were performed to evaluate the prognoses. MIG-7 knockdown osteosarcoma cells were used for cell proliferation, apoptosis, migration, invasiveness and VM formation assays. A spontaneously metastasizing cell line-derived orthotopic xenograft mouse model was established to evaluate the effect of MIG-7 knockdown on tumorigenesis, VM formation and lung metastasis. MIG-7 expression was associated with VM formation. There were significant differences in overall and metastasis-free survival between the MIG-7-positive and MIG-7-negative groups. The MIG-7 expression was shown to be an independent indicator of both overall and metastasis-free survival. In vitro knockdown of MIG-7 dramatically reduced migration, invasion and VM formation in osteosarcoma cells without any significant effect on cell proliferation and apoptosis. MIG-7 knockdown also exhibited potent antitumor, antimetastasis and anti-VM effects in the orthotopic mouse model of 143B osteosarcoma. Therefore, MIG-7 serves as an independent unfavorable prognostic indicator in osteosarcoma patients and MIG-7 is an important mediator of osteosarcoma VM formation.

Zhang H, Liu W, Wang Z, et al.
MEF2C promotes gefitinib resistance in hepatic cancer cells through regulating MIG6 transcription.
Tumori. 2018; 104(3):221-231 [PubMed] Related Publications
INTRODUCTION: Mitogen-inducible gene 6 ( MIG6) holds a special position in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. As MIG6 regulates the activity of EGFR signal pathway negatively, high level of MIG6 can increase the EGFR TKI resistance of cancer cells, and limit the therapeutic action of EGFR TKI, such as gefitinib or erlotinib. Therefore, better understanding of the molecular mechanisms underlying the regulation of EGFR TKI resistance holds great value in cancer therapy.
METHODS: In our study, we mainly explored the function of transcription activator, myocyte enhancer factor 2C (MEF2C), on MIG6 expression as well as gefitinib-resistant ability of hepatic cancer cells.
RESULTS: Our results indicated that both MEF2C and MIG6 could be upregulated in gefitinib-resistant cancer tissues and cancer cell lines compared with gefitinib-sensitive ones. Chromatin immunoprecipitation assay and dual luciferase assay showed that MEF2C could bind to the MEF2C element in the promoter sequence of MIG6 and promote the transcription of MIG6. This effect increased the gefitinib-resistant ability of cancer cells. Therefore, MEF2C knockdown inhibited the gefitinib resistance and limited the proliferation of hepatic cancer cells in vitro and in vivo, while overexpression of MEF2C showed opposite effect on cancer cell proliferation.
CONCLUSION: Our study provides novel insight into the regulation mechanism of MIG6 and suggests potential implications for the therapeutic strategies of gefitinib resistance through inhibiting MEF2C in hepatic cancer cells.

Zhang C, Li Z, Xu L, et al.
CXCL9/10/11, a regulator of PD-L1 expression in gastric cancer.
BMC Cancer. 2018; 18(1):462 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.
METHODS: Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.
RESULTS: Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.
CONCLUSIONS: CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues.

Chen E, Qin X, Peng K, et al.
Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis.
Cell Physiol Biochem. 2018; 45(5):1731-1746 [PubMed] Related Publications
BACKGROUND/AIMS: Breast cancer is a common cause of cancer mortality throughout the world. The cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC is one of four chemokine families involved in mediating survival, angiogenesis, and immunosensitization by chemoattracting leukocytes, and it incentivizes tumor cell growth, invasion and metastasis in the tumor microenvironment. However, the differential expression profiles and prognostic values of these chemokines remains to be elucidated.
METHODS: In this study, we compared transcriptional CXC chemokines and survival data of patients with breast carcinoma (BC) using the ONCOMINE dataset, Kaplan-Meier Plotter, TCGA and cBioPortal.
RESULTS: We discovered increased mRNA levels for CXCL8/10/11/16/17, whereas mRNA expression of CXCL1/2/3/4/5/6/7/12/14 was lower in BC patients compared to non-tumor tissues. Kaplan-Meier plots revealed that high mRNA levels of CXCL1/2/3/4/5/6/7/12/14 correlate with relapse-free survival (RFS) in all types of BC patients. Conversely, high CXCL8/10/11 predicted worse RFS in BC patients. Significantly, high transcription levels of CXCL9/12/13/14 conferred an overall survival (OS) advantage in BC patients, while high levels of CXCL8 demonstrated shorter OS in all BC sufferers.
CONCLUSIONS: Integrative bioinformatics analysis suggests that CXCL8/12/14 are potential suitable targets for precision therapy in BC patients compared to other CXC chemokines.

Cremonesi E, Governa V, Garzon JFG, et al.
Gut microbiota modulate T cell trafficking into human colorectal cancer.
Gut. 2018; 67(11):1984-1994 [PubMed] Related Publications
OBJECTIVE: Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers.
DESIGN: Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing.
RESULTS: CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival.
CONCLUSIONS: Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

Lai Q, Wang H, Li A, et al.
Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells.
Oncogene. 2018; 37(17):2302-2312 [PubMed] Related Publications
IFN-γ-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-γ related genes IRF1/8 and IFN-α/β-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation. Interestingly, decitibine (DAC) as methylation inhibitor could hypomethylate IRF1/7 to restore PD-L1 level. Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-γ though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7. The supplement of DAC to anti-PD-1 therapy in vivo improve the efficiency of anti-tumor with less methylated IRF1/7, more interferon-related genes expression (e.g., CXCL9) and IFN-γ/CD8+ T-cells infiltrations, suggesting that additional treatment of DAC could rescue the ability to response to IFN in lung cancer patients with anti-PD-1/L1 therapy resistance.

de Mingo Pulido Á, Gardner A, Hiebler S, et al.
TIM-3 Regulates CD103
Cancer Cell. 2018; 33(1):60-74.e6 [PubMed] Free Access to Full Article Related Publications
Intratumoral CD103

Michaelsen SR, Urup T, Olsen LR, et al.
Molecular profiling of short-term and long-term surviving patients identifies CD34 mRNA level as prognostic for glioblastoma survival.
J Neurooncol. 2018; 137(3):533-542 [PubMed] Related Publications
Despite extensive treatment, overall survival (OS) for glioblastoma (GBM) remains poor. A small proportion of patients present long survival over 3 years, but the underlying molecular background separating these long-term survivors (LTS) from short-term survivors (STS) are insufficiently understood. Accordingly, study aim was to identify independent prognostic biomarkers for survival. Study cohort consisted of 93 primary GBM patients treated with radiation-, chemo- and bevacizumab therapy, among which 14 STS (OS ≤ 12 months) and 6 LTS (OS ≥ 36 months) were identified, all confirmed being IDH wild-type. RNA expression levels in diagnostic tumor specimen for 792 genes were analyzed by NanoString technology. While no differences were found with regard to GBM subtype between LTS versus STS, comparative analysis of individual genes identified 14 significantly differently expressed candidate genes. Univariate analysis in the whole patient cohort found that 12 of these were significantly associated with OS, of which increased IFNG, CXCL9, LGALS4, CD34 and decreased MGMT levels remained significant associated with prolonged OS in multivariate analysis correcting for known prognostic variables. Validation analyses in an independent dataset from the AVAglio study confirmed CD34 as significant in comparative analysis between STS and LTS patients and as an independent prognostic factor. Analysis of this dataset further supported CD34 expression to be associated with improved bevacizumab efficacy, while CD34 immunohistochemistry indicated variation in CD34 expression to result primarily from varying tumor vascularization. Collectively, CD34 expression candidates as a prognostic biomarker in GBM able to identify survival outliers and could also be predictive for efficacy of bevacizumab.

Li Z, Liu J, Li L, et al.
Epithelial mesenchymal transition induced by the CXCL9/CXCR3 axis through AKT activation promotes invasion and metastasis in tongue squamous cell carcinoma.
Oncol Rep. 2018; 39(3):1356-1368 [PubMed] Related Publications
The present study aimed to assess the induction of epithelial-mesenchymal transition (EMT), invasion, and metastasis by the chemokine CXCL9/receptor CXCR3 axis in tongue squamous cell carcinoma (TSCC), unveiling the underlying mechanisms and providing new insights into the prevention and treatment of oral cancer metastasis. The expression levels of CXCL9 and CXCR3 in TSCC tissue specimens were determined by immunohistochemistry, assessing differences between samples with cervical lymph node metastasis and those without. Moreover, protein expression or activity in the TSCC Cal-27 cell line was controlled by neutralizing antibodies, gene transfection, or knock-out. Then, alterations of cell proliferation, migration, invasion, and the cytoskeleton were analyzed by CCK-8, cell scratch, Transwell, and cyto-skeleton staining assays, respectively. Alterations of EMT markers (E-cadherin and vimentin) in Cal-27 cells were detected by immunofluorescence and western blotting. In addition, western blotting was utilized to detect protein expression levels of Akt2, p-Akt2, eIF4E and p-eIF4E, and to explore the regulatory roles and mechanisms of the CXCL9/CXCR3 axis in invasion and metastasis. Significantly increased expression levels of CXCL9 and CXCR3 were detected in tissue specimens with lymph node metastasis compared with those without (P<0.01). Overexpression of CXCL9/CXCR3 in Cal-27 cells resulted in cytoskeleton alterations, decreased E-cadherin expression, increased vimentin levels, enhanced migration and invasion (P<0.05), and increased phosphorylated Akt2 and eIF4E levels (P<0.05). These results revealed that in TSCC, the CXCL9/CXCR3 axis could activate the Akt signaling pathway, with EMT and cytoskeleton rearrangement, promoting invasion and metastasis.

Qu B, Sheng G, Guo L, et al.
MIG7 is involved in vasculogenic mimicry formation rendering invasion and metastasis in hepatocellular carcinoma.
Oncol Rep. 2018; 39(2):679-686 [PubMed] Related Publications
Migration-inducing gene 7 (MIG7) is highly expressed and is implicated in multiple malignant tumors with vasculogenic mimicry (VM) which renders possible routes without the endothelium for invasion and metastasis. However, there are few reports in the literature describing the relationship between MIG7 expression and VM formation in hepatocellular carcinoma (HCC). In the present study, we found a significantly positive correlation between MIG7 expression and VM in 40 HCC specimens. Three-dimensional (3D) culture showed that VM formation in the HCC cell line MHCC-97H with high metastatic potential was enhanced to a greater extent than that of MHCC-97L and Huh-7 with low and non-metastatic potential. There was no VM formation in human normal hepatocyte line L-02. Moreover, MIG7 expression was higher in MHCC-97H than in MHCC-97L and Huh-7 cells and non-detectable in L-02 cells. MIG7 knockdown in MHCC-97H cells reduced VM formation, and weakened the invasive properties accompanying the enhanced cellular adhesion. Notably, there was no significant effect of endostatin (ES), a broad-spectrum angiogenesis inhibitor applied to clinical treatment, on both MIG7 expression and VM formation. Thus, the present study presents a causal link between MIG7 expression and VM formation in HCC, suggesting a potential treatment target for invasion and metastasis.

Febvre-James M, Lecureur V, Augagneur Y, et al.
Repression of interferon β-regulated cytokines by the JAK1/2 inhibitor ruxolitinib in inflammatory human macrophages.
Int Immunopharmacol. 2018; 54:354-365 [PubMed] Related Publications
Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines (n=84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) (n=44), 61.4% (n=27) were repressed by 5μM ruxolitinib. The major inflammatory cytokines, interleukin (IL) 6 and tumor necrosis factor α, were notably down-regulated by ruxolitinib at both the mRNA and protein level. Other repressed cytokines included IL27 and the chemokines CCL2, CXCL9, CXCL10 and CXCL11, but not IL1β. The interferon (IFN) β/JAK/signal transducer and activator of transcription (STAT) pathway, well-activated by LPS in human macrophages as demonstrated by increased secretion of IFNβ, STAT1 phosphorylation, and up-regulation of reference IFNβ-responsive genes, was concomitantly blocked by the JAK inhibitor. Most of cytokines targeted by ruxolitinib were shown to be regulated by IFNβ in a JAK-sensitive manner. In addition, counteracting the IFNβ/JAK/STAT cascade using a blocking monoclonal antibody directed against IFNβ receptor resulted in a similar profile of cytokine repression to that observed in response to the JAK inhibitor. Overall, these data provide evidence for ruxolitinib-mediated repression of inflammatory cytokines in human macrophages through inhibition of the LPS/IFNβ/JAK/STAT signalling pathway, which probably contributes to the anti-inflammatory effects of the JAK inhibitor.

Liu R, Lu Z, Gu J, et al.
MicroRNAs 15A and 16-1 Activate Signaling Pathways That Mediate Chemotaxis of Immune Regulatory B cells to Colorectal Tumors.
Gastroenterology. 2018; 154(3):637-651.e7 [PubMed] Related Publications
BACKGROUND & AIMS: B cells infiltrate tumors, but little is known about how they affect tumor growth and progression. microRNA15A (MIR15A or miRNA15A) and microRNA16-1 (MIR16-1 or miRNA16-1) regulate cell proliferation, apoptosis, and drug resistance. We investigated their involvement in B-cell-mediated immune suppression by colorectal tumors.
METHODS: Mice with disruptions of the gene cluster that encodes MIR15A and MIR16-1 (knockout mice), and control (C57BL/B6) mice were given azoxymethane with dextran sodium sulfate (AD) to induce formation of colorectal tumors. Mice were given anti-CD20 to delete B cells, or injections of agomir to increase MIR15A and MIR16-1. Proliferation of CD8
RESULTS: Tumors that developed in knockout mice following administration of AD were larger and contained greater numbers of B cells than tumors that grew in control mice. Most of the B cells in the tumors were positive for immunoglobulin A (IgA
CONCLUSIONS: We found increased levels of MIR15A and MIR16-1 to reduce numbers of IgA

Yoo JY, Yang WS, Lee JH, et al.
MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells.
Oncogene. 2018; 37(2):255-262 [PubMed] Free Access to Full Article Related Publications
Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4-resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2f

Li H, Chen H, Wang H, et al.
MicroRNA-374a Promotes Hepatocellular Carcinoma Cell Proliferation by Targeting Mitogen-Inducible Gene 6 (MIG-6).
Oncol Res. 2018; 26(4):557-563 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a disease with poor prognosis rates and ineffective therapeutic options. Previous studies have reported the involvement of mitogen-inducible gene 6 (MIG-6) as a negative regulator in tumor formation. MicroRNAs (miRNAs) play crucial roles in the development of different types of cancer. However, the underlying mechanisms of miRNAs in HCC are poorly understood. This study was aimed to investigate the role of miR-374a in HCC and its role in the regulation of expression of MIG-6. The results showed that MIG-6 overexpression significantly inhibited cell viability of HepG2 cells after 4 days posttransfection. Moreover, MIG-6 was a direct target of miR-374a, and the expression of MIG-6 was remarkably downregulated by the overexpression of miR-374a in HepG2 cells. Furthermore, we found that overexpression of miR-374a promoted cell viability; however, the protective effect was abolished by MIG-6 overexpression. In addition, overexpression of miR-374a activated the EGFR and AKT/ERK signaling pathways by regulation of MIG-6. Our findings suggest that miR-374a could promote cell viability by targeting MIG-6 and activating the EGFR and AKT/ERK signaling pathways. These data provide a promising therapeutic strategy for HCC treatment.

Iddawela M, Rueda O, Eremin J, et al.
Integrative analysis of copy number and gene expression in breast cancer using formalin-fixed paraffin-embedded core biopsy tissue: a feasibility study.
BMC Genomics. 2017; 18(1):526 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: An absence of reliable molecular markers has hampered individualised breast cancer treatments, and a major limitation for translational research is the lack of fresh tissue. There are, however, abundant banks of formalin-fixed paraffin-embedded (FFPE) tissue. This study evaluated two platforms available for the analysis of DNA copy number and gene expression using FFPE samples.
METHODS: The cDNA-mediated annealing, selection, extension, and ligation assay (DASL™) has been developed for gene expression analysis and the Molecular Inversion Probes assay (Oncoscan™), were used for copy number analysis using FFPE tissues. Gene expression and copy number were evaluated in core-biopsy samples from patients with breast cancer undergoing neoadjuvant chemotherapy (NAC).
RESULTS: Forty-three core-biopsies were evaluated and characteristic copy number changes in breast cancers, gains in 1q, 8q, 11q, 17q and 20q and losses in 6q, 8p, 13q and 16q, were confirmed. Regions that frequently exhibited gains in tumours showing a pathological complete response (pCR) to NAC were 1q (55%), 8q (40%) and 17q (40%), whereas 11q11 (37%) gain was the most frequent change in non-pCR tumours. Gains associated with poor survival were 11q13 (62%), 8q24 (54%) and 20q (47%). Gene expression assessed by DASL correlated with immunohistochemistry (IHC) analysis for oestrogen receptor (ER) [area under the curve (AUC) = 0.95], progesterone receptor (PR)(AUC = 0.90) and human epidermal growth factor type-2 receptor (HER-2) (AUC = 0.96). Differential expression analysis between ER+ and ER- cancers identified over-expression of TTF1, LAF-4 and C-MYB (p ≤ 0.05), and between pCR vs non-pCRs, over-expression of CXCL9, AREG, B-MYB and under-expression of ABCG2.
CONCLUSION: This study was an integrative analysis of copy number and gene expression using FFPE core biopsies and showed that molecular marker data from FFPE tissues were consistent with those in previous studies using fresh-frozen samples. FFPE tissue can provide reliable information and will be a useful tool in molecular marker studies.
TRIAL REGISTRATION: Trial registration number ISRCTN09184069 and registered retrospectively on 02/06/2010.

Doorduijn EM, Sluijter M, Salvatori DC, et al.
CD4
Cancer Immunol Res. 2017; 5(8):642-653 [PubMed] Related Publications
One of the next challenges in cancer immunotherapy is the resistance of tumors to T-cell-based treatments through loss of MHC class I. Here, we show that under these circumstances, the Toll-like receptor (TLR)-7/8 ligand imiquimod, but not the TLR3 ligand poly I:C or TLR9 ligand CpG, mediated an effective antitumor response. The rejection of these immune-escaped cancers was mediated by NK cells and CD4

P Vassilakopoulos T, Levidou G, Milionis V, et al.
Thioredoxin-1, chemokine (C-X-C motif) ligand-9 and interferon-γ expression in the neoplastic cells and macrophages of Hodgkin lymphoma: clinicopathologic correlations and potential prognostic implications.
Leuk Lymphoma. 2017; 58(9):1-13 [PubMed] Related Publications
Expression of thioredoxin-1 (TXN) and CXCL9 is not restricted to THRLBCL macrophages, but may be observed in histiocytes and neoplastic (HRS) cells of EBV + mixed cellularity (MC) classical Hodgkin lymphoma (cHL) and nodular lymphocyte predominant HL. We aimed to validate and extend the above observations in 174 cHL patients evaluating the immunohistochemical expression of TXN, CXCL9 and IFN-γ. HRS-cell CXCL9 expression was higher in latent membrane protein-1 (LMP1)+, MC and Stage IV. TXN and CXCL9 expression by cHL histiocytes was more frequent in LMP1+, MC and older patients (only for CXCL9). TXN expression by HRS cells (≥80%) was independently associated with better failure-free survival. In conclusion, markers of TCHRLBCL histiocytes (TXN, CXCL9), as well as IFN-γ are also expressed by histiocyte subsets and neoplastic cells of cHL. The expression of some of them is more prominent in EBV + MC, but not restricted to this subtype. The prognostic implication of TXN needs further evaluation.

Ando H, Miyamoto T, Kashima H, et al.
Panobinostat Enhances Growth Suppressive Effects of Progestin on Endometrial Carcinoma by Increasing Progesterone Receptor and Mitogen-Inducible Gene-6.
Horm Cancer. 2017; 8(4):257-267 [PubMed] Related Publications
Although progestin has been used to treat endometrial hyperplasia and endometrial carcinoma (EC), its therapeutic efficacy is limited. In order to improve this, the underlining mechanisms of the effects of progestin need to be elucidated in more detail. In the present study, we examined the involvement of mitogen-inducible gene-6 (MIG6), a negative regulator of the EGF receptor, in the progestin-mediated growth suppression of endometrial epithelia. The immunohistochemical expression of MIG6 was elevated in the early to mid-secretory phases of normal endometrium and also with endometrial hyperplasia after medroxyprogesterone acetate (MPA) therapy. The addition of progesterone (P4) to progesterone receptor (PR)-positive EC cells reduced the viability and induced MIG6 messenger RNA (mRNA) and protein expression. The silencing of MIG6 using siRNA eliminated the P4-mediated reduction of EC cell viability, indicating that MIG6 is an essential downstream component of PR-mediated growth suppression. In order to enhance PR-driven signals, we examined the effects of histone deacetylase (HDAC) inhibitors because histone acetylation has been shown to increase the expression of PR. The addition of three HDAC inhibitors (panobinostat, LBH589; trichostatin A, TSA; suberoylanilide hydroxamic acid, SAHA) decreased the viability of EC cells and up-regulated the expression of PR and MIG6, and these effects were the strongest with LBH589. The addition of LBH589 and MPA synergistically decreased the viability and increased apoptosis in EC cells. These results indicate that LBH589 has potential as an enhancer of progestin therapy via the up-regulation of PR and MIG6.

Li Z, Qu L, Luo W, et al.
Mig-6 is down-regulated in HCC and inhibits the proliferation of HCC cells via the P-ERK/Cyclin D1 pathway.
Exp Mol Pathol. 2017; 102(3):492-499 [PubMed] Related Publications
The ablation of Mig-6 has been shown to induce tumor formation in various tissues. However, the relationships between Mig-6 expression, clinical pathological factors, and prognosis have not been clarified in hepatocellular carcinoma (HCC), and the mechanism by which Mig-6 regulates the proliferation of HCC cells has not been reported. In this study, we investigated the clinical significance of the loss of Mig-6 expression in HCC and the mechanism underlying the inhibition of cell proliferation by Mig-6. The down-regulation of Mig-6 correlated significantly with large tumors, a more advanced BCLC stage, and a more advanced TNM stage, and low Mig-6 expression predicted significantly reduced survival. Low Mig-6 expression and high Cyclin D1 expression were independent predictors for survival. The overexpression of Mig-6 led to significant G

Han X, Parker TL
Anti-inflammatory activity of clove (Eugenia caryophyllata) essential oil in human dermal fibroblasts.
Pharm Biol. 2017; 55(1):1619-1622 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Clove (Eugenia caryophyllata Thunb. [Myrtaceae]) essential oil (CEO) has been shown to possess antimicrobial, antifungal, antiviral, antioxidant, anti-inflammatory and anticancer properties. However, few studies have focused on its topical use.
OBJECTIVE: We investigated the biological activity of a commercially available CEO in a human skin disease model.
MATERIALS AND METHODS: We evaluated the effect of CEO on 17 protein biomarkers that play critical roles in inflammation and tissue remodelling in a validated human dermal fibroblast system, which was designed to model chronic inflammation and fibrosis. Four concentrations of CEO (0.011, 0.0037, 0.0012, and 0.00041%, v/v) were studied. The effect of 0.011% CEO on genome-wide gene expression was also evaluated.
RESULTS AND DISCUSSION: CEO at a concentration of 0.011% showed robust antiproliferative effects on human dermal fibroblasts. It significantly inhibited the increased production of several proinflammatory biomarkers such as vascular cell adhesion molecule-1 (VCAM-1), interferon γ-induced protein 10 (IP-10), interferon-inducible T-cell α chemoattractant (I-TAC), and monokine induced by γ interferon (MIG). CEO also significantly inhibited tissue remodelling protein molecules, namely, collagen-I, collagen-III, macrophage colony-stimulating factor (M-CSF), and tissue inhibitor of metalloproteinase 2 (TIMP-2). Furthermore, it significantly modulated global gene expression and altered signalling pathways critical for inflammation, tissue remodelling, and cancer signalling processes. CEO significantly inhibited VCAM-1 and collagen III at both protein and gene expression levels.
CONCLUSIONS: This study provides important evidence of CEO-induced anti-inflammatory and tissue remodelling activity in human dermal fibroblasts. This study also supports the anticancer properties of CEO and its major active component eugenol.

Goodyear OC, Essex S, Seetharam A, et al.
Neoplastic plasma cells generate an inflammatory environment within bone marrow and markedly alter the distribution of T cells between lymphoid compartments.
Oncotarget. 2017; 8(18):30383-30394 [PubMed] Free Access to Full Article Related Publications
Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) are characterised by the accumulation of malignant plasma cells within bone marrow and lead to a range of abnormalities in the peripheral blood T cell repertoire. We investigated the level of inflammatory chemokines within the bone marrow and blood of patients with MGUS and MM and related this to the pattern of chemokine receptor expression on T cells in both compartments.The expression of a wide range of chemokine ligands for CXCR3 and CCR4 was markedly increased within the bone marrow of patients with MGUS and MM compared to healthy donors. The most marked effects were seen for CCL4 and CXCL9 which were increased by 4 and 6 fold respectively in the bone marrow of patients with myeloma. The expression of CXCR3 and CCR4, the major TH1 and TH2-associated chemokine receptors, was increased substantially on T cells within the bone marrow of patients whereas the percentage of CXCR3-expressing T cells within blood was correspondingly decreased. The presence of even small numbers of neoplastic plasma cells or associated stroma can therefore generate an inflammatory chemokine tumour microenvironment. This leads to the selective recruitment or retention of specific T cell subsets which is likely to underlie many of the features regarding the peripheral T cell repertoire in myeloma and may also contribute to the immune suppression associated with this disease. This local inflammatory reaction may represent a tumour-specific immune response or may itself play an important role in tumour progression and as such may offers a potential novel target for therapeutic intervention.

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