Gene Summary

Gene:CCL22; C-C motif chemokine ligand 22
Aliases: MDC, ABCD-1, SCYA22, STCP-1, DC/B-CK, A-152E5.1
Summary:This antimicrobial gene is one of several Cys-Cys (CC) cytokine genes clustered on the q arm of chromosome 16. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene displays chemotactic activity for monocytes, dendritic cells, natural killer cells and for chronically activated T lymphocytes. It also displays a mild activity for primary activated T lymphocytes and has no chemoattractant activity for neutrophils, eosinophils and resting T lymphocytes. The product of this gene binds to chemokine receptor CCR4. This chemokine may play a role in the trafficking of activated T lymphocytes to inflammatory sites and other aspects of activated T lymphocyte physiology. [provided by RefSeq, Sep 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-C motif chemokine 22
Source:NCBIAccessed: 31 August, 2019


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 31 August 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: CCL22 (cancer-related)

Kumar N, Zhao D, Bhaumik D, et al.
Quantification of intrinsic subtype ambiguity in Luminal A breast cancer and its relationship to clinical outcomes.
BMC Cancer. 2019; 19(1):215 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: PAM50 gene profiling assigns each cancer to a single intrinsic subtype. However, individual cancers vary in their adherence to a prototype, and due to bulk tissue sampling, some may exhibit expression patterns that indicate intra-tumor admixture of multiple subtypes. Our objective was to develop admixture metrics from PAM50 gene expression profiles in order to stratify Luminal A (LumA) cases according to their degree of subtype admixture, and then relate such admixture to clinical and molecular variables.
METHODS: We re-constructed scaled, normalized PAM50 profiles for 1980 cases (674 LumA) in the METABRIC cohort and for each case computed its Mahalanobis (M-) distance from its assigned centroid and M-distance from all other centroids. We used t-SNE plots to visualize overlaps in subtype clustering. With Normal-like cases excluded, we developed two metrics: Median Distance Criteria (MDC) classified pure cases as those located within the 50th percentile of the LumA centroid and > =50th percentile from any other centroid. Distance Ratio Criteria (DRC) was computed as the ratio of M-distances from the LumA centroid to the nearest non-assigned centroid. Pure and admixed LumA cases were compared on clinical/molecular traits. TCGA LumA cases (n = 509) provided independent validation.
RESULTS: Compared to pure cases in METABRIC, admixed ones had older age at diagnosis, larger tumor size, and higher grade and stage. These associations were stronger for the DRC metric compared to MDC. Admixed cases were associated with HER2 gain, high proliferation, higher PAM50 recurrence scores, more frequent TP53 mutation, and less frequent PIK3CA mutation. Similar results were observed in the TCGA validation cohort, which also showed a positive association between admixture and number of clonal populations estimated by PyClone. LumA-LumB confusion predominated, but other combinations were also present. Degree of admixture was associated with overall survival in both cohorts, as was disease-free survival in TCGA, independent of age, grade and stage (HR = 2.85, Tertile 3 vs.1).
CONCLUSIONS: Luminal A breast cancers subgrouped based on PAM50 subtype purity support the hypothesis that admixed cases have worse clinical features and survival. Future analyses will explore more extensive genomic metrics for admixture and their spatial significance within a single tumor.

Radhakrishnan H, Walther W, Zincke F, et al.
MACC1-the first decade of a key metastasis molecule from gene discovery to clinical translation.
Cancer Metastasis Rev. 2018; 37(4):805-820 [PubMed] Related Publications
Deciphering the paths to metastasis and identifying key molecules driving this process is one important issue for understanding and treatment of cancer. Such a key driver molecule is Metastasis Associated in Colon Cancer 1 (MACC1). A decade long research on this evolutionarily conserved molecule with features of a transcription factor as well as an adapter protein for versatile protein-protein interactions has shown that it has manifold properties driving tumors to their metastatic stage. MACC1 transcriptionally regulates genes involved in epithelial-mesenchymal transition (EMT), including those which are able to directly induce metastasis like c-MET, impacts tumor cell migration and invasion, and induces metastasis in solid cancers. MACC1 has proven as a valuable biomarker for prognosis of metastasis formation linked to patient survival and gives promise to also act as a predictive marker for individualized therapies in a broad variety of cancers. This review discusses the many features of MACC1 in the context of the hallmarks of cancer and the potential of this molecule as biomarker and novel therapeutic target for restriction and prevention of metastasis.

Gerashchenko GV, Grygoruk OV, Kononenko OA, et al.
Expression pattern of genes associated with tumor microenvironment in prostate cancer.
Exp Oncol. 2018; 40(4):315-322 [PubMed] Related Publications
AIM: To assess relative expression (RE) levels of CAF-, TAM-specific, immune defense-associated genes in prostate tumors and to show correlation of RE with clinical, pathological and molecular characteristics, with the aim to define clinically significant specific alterations in a gene expression pattern.
METHODS: RE of 23 genes was analyzed by a quantitative polymerase chain reaction in 37 freshly frozen samples of prostate cancer tissues of a different Gleason score (GS) and at various tumor stages, compared with RE in 37 paired conventionally normal prostate tissue (CNT) samples and 20 samples of prostate adenomas.
RESULTS: Differences in RE were shown for 11 genes out of 23 studied, when tumor samples were compared with corresponding CNTs. 7 genes, namely ACTA2, CXCL14, CTGF, THY1, FAP, CD163, CCL17 were upregulated in tumors. 4 genes, namely CCR4, NOS2A, MSMB, IL1R1 were downregulated in tumors. 14 genes demonstrated different RE in TNA at different stages: CXCL12, CXCL14, CTGF, FAP, HIF1A, THY1, CCL17, CCL22, CCR4, CD68, CD163, NOS2A, CTLA4, IL1R1. RE changes of 9 genes - CXCL12, CXCL14, HIF1A, CCR4, CCL17, NOS2A, CTLA4, IL1R1, IL2RA - were found in tumors with different GS. Moreover, 9 genes showed differences in RE in TNA, dependently on the presence or absence of the TMPRSS2/ERG fusion and 7 genes showed differences in RE of groups with differential PTEN expression. Significant correlations were calculated between RE of 9 genes in adenocarcinomas and the stage, and GS; also, between RE of 2 genes and the fusion presence; and between RE of 4 genes and PTEN expression.
CONCLUSIONS: Several gene expression patterns were identified that correlated with the GS, stage and molecular characteristics of tumors, i.e. presence of the TMPRSS2/ERG fusion and alterations in PTEN expression. These expression patterns can be used for molecular profiling of prostate tumors, with the aim to develop personalized medicine approaches. However, the proposed profiling requires a more detailed analysis and a larger cohort of patients with prostate tumor.

Mei LH, Yang G, Fang F
Hyperbaric Oxygen Combined with 5-Aminolevulinic Acid Photodynamic Therapy Inhibited Human Squamous Cell Proliferation.
Biol Pharm Bull. 2019; 42(3):394-400 [PubMed] Related Publications
The photodynamic therapy (PDT) depends on the presence of molecular oxygen. Thus, the efficiency of PDT is limited in anoxic regions of tumor tissue and vascular shutdown. It is reported the use of hyperbaric oxygen (HBO) may enhance the efficiency of PDT. However, there are rarely studies about utilizing HBO plus PDT for treatment with human squamous cell carcinoma (SCC). Therefore, this study aimed to investigate and compare the therapeutic effect of combined therapy and PDT alone treatment. Multiple cellular and molecular biology techniques were used in the current study such as CCK-8, Western blotting, flow cytometry, monodansylcadaverine (MDC) staining and immunofluorescence assay. The results of combination index indicated that HBO combination with PDT synergistically inhibited A431 cells proliferation in vitro. In addition, we found that HBO significantly enhanced PDT-induced cell apoptosis via increasing the active caspase-3, active caspase-9, Apaf-1 and Bax levels and down-regulating Bcl-2. Meanwhile, the result of MDC and immunofluorescence assay confirmed that HBO increased PDT-induced autophagosome formation in A431 cells. Interestingly, autophagy inhibitor 3-methyladenine (3-MA) further increased combination-induced cell apoptosis by increasing the levels of active-caspase 9 and Apaf-1. Our results showed that HBO combined with PDT markedly induced A431 cells apoptosis and autophagy. Nevertheless, autophagy play a pro-survival role against apoptosis. Thus, HBO combination with PDT may constitute a promising approach to treat human squamous cell carcinoma in the future.

Kuehnemuth B, Piseddu I, Wiedemann GM, et al.
CCL1 is a major regulatory T cell attracting factor in human breast cancer.
BMC Cancer. 2018; 18(1):1278 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer.
METHODS: One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed.
RESULTS: Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg (p< 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant.
CONCLUSIONS: We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer.

Ye L, Zhou J, Zhao W, et al.
Gambogic acid-induced autophagy in nonsmall cell lung cancer NCI-H441 cells through a reactive oxygen species pathway.
J Cancer Res Ther. 2018; 14(Supplement):S942-S947 [PubMed] Related Publications
Aim of the Study: Garcinia hanburyi is a traditional herbal medicine with activities of anti-inflammation and hemostasis used by people in South Asia. Gambogic acid (GA) is the main active component extracted from it, which has anticancer and anti-inflammatory effects. The aim of the current study is to investigate the molecular mechanisms of GA's effective anticancer activity.
Materials and Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to measure cell proliferation. Apoptosis induced by GA was analyzed by flow cytometry. In addition, monodansylcadaverine (MDC) and 2',7'-dichlorofluorescein diacetate were used to evaluate autophagy and reactive oxygen species (ROS) generation, respectively.
Results: GA could significantly inhibit nonsmall cell lung cancer (NSCLC) NCI-H441 cell growth. In addition, GA induced NCI-H441 cells autophagy, confirmed by MDC staining, upregulation of Beclin 1 (initiation factor for autophagosome formation), and conversion of LC3 I to LC3 II (autophagosome marker). Moreover, generated ROS was induced by GA in NCI-H441 cells and the ROS scavenger N-acetylcysteine reversed GA-induced autophagy and restored the cell survival, which indicated GA-induced autophagy in NCI-H441 cells through an ROS-dependent pathway. In addition, in vivo results further indicated that GA significantly inhibited the growth of NCI-H441 xenografts.
Conclusions: The results shed new light on the interaction between ROS generation and autophagy in NSCLC cells and provide theoretical support for the usage of GA in clinical treatment.

Zhou XT, Pu ZJ, Liu LX, et al.
Inhibition of autophagy enhances adenosine‑induced apoptosis in human hepatoblastoma HepG2 cells.
Oncol Rep. 2019; 41(2):829-838 [PubMed] Free Access to Full Article Related Publications
In cancer research, autophagy acts as a double‑edged sword: it increases cell viability or induces cell apoptosis depending upon the cell context and functional status. Recent studies have shown that adenosine (Ado) has cytotoxic effects in many tumors. However, the role of autophagy in Ado‑induced apoptosis is still poorly understood. In the present study, Ado‑induced apoptotic death and autophagy in hepatoblastoma HepG2 cells was investigated and the relationship between autophagy and apoptosis was identified. In the present study, it was demonstrated that Ado inhibited HepG2 cell growth in a time‑ and concentration‑dependent manner and activated endoplasmic reticulum (ER) stress, as indicated by G0/G1 cell cycle arrest, the increased mRNA and protein levels of GRP78/BiP, PERK, ATF4, CHOP, cleaved caspase‑3, cytochrome c and the loss of mitochon-drial membrane potential (ΔΨm). Ado also induced autophagic flux, revealed by the increased expression of the autophagy marker microtubule‑associated protein 1 light chain 3‑II (LC3‑II), Beclin‑1, autophagosomes, and the degradation of p62, as revealed by western blot analysis and macrophage‑derived chemokine (MDC) staining. Blocking autophagy using LY294002 notably entrenched Ado‑induced growth inhibition and cell apoptosis, as demonstrated with the increased expression of cytochrome c and p62, and the decreased expression of LC3‑II. Conversely, the autophagy inducer rapamycin alleviated Ado‑induced apoptosis and markedly increased the ΔΨm. Moreover, knockdown of AMPK with si‑AMPK partially abolished Ado‑induced ULK1 activation and mTOR inhibition, and thus reinforced CHOP expression and Ado‑induced apoptosis. These results indicated that Ado‑induced ER stress resulted in apoptosis and autophagy concurrently. The AMPK/mTOR/ULK1 signaling pathway played a protective role in the apoptotic procession. Inhibition of autophagy may effectively enhance the anticancer effect of Ado in human hepatoblastoma HepG2 cells.

Zeng C, Chen L, Chen B, et al.
Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(12):1266-1273 [PubMed] Related Publications
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder characterized by memory deficits, psychiatric symptoms, and autonomic instability. The lack of suitable biomarkers targeting anti-NMDAR encephalitis makes the immunotherapy and prognosis challenging. In this study, we found that the Th17 cells were significantly accumulated in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients than that of control individuals. The concentration of the cytokines and chemokines including interleukin (IL)-1β, IL-17, IL-6, and CXCL-13 were significantly increased in the CSF of anti-NMDAR encephalitis patients. IL-6 and IL-17 were found to promote the differentiation of CD4+ T cells into Th17 lineage. The chemotaxis assay showed that CCL20 and CCL22 play essential roles in the migration of Th17 cells. Notably, the correlation between the expression of IL-17 and the outcome of anti-NMDAR encephalitis patients was analyzed. The data showed that high level of IL-17 was significantly correlated with the limited response to the treatment and relapse of anti-NMDAR encephalitis patients. Our results suggested the potential important involvement of IL-17 in anti-NMDAR encephalitis.

Cheng Y, Li Z, Xie J, et al.
MiRNA-224-5p inhibits autophagy in breast cancer cells via targeting Smad4.
Biochem Biophys Res Commun. 2018; 506(4):793-798 [PubMed] Related Publications
BACKGROUND/AIMS: Autophagy is known as a protective intracellular procedure, which can be regulated by several factors. MiRNA has been suggested as a potential element to mediate autophagy pathway in carcinomas. Our study was aim to investigate the role of autophagy in breast cancer cells and identify the involved molecular mechanism METHODS: The expression of LC3I/II, SQSTM1 and Smad4 were detected by western blot. The mRNA level were quantified by real-time PCR. MDC staining was used to directly visualize autophagosome formation. Target Scan 7.2 was used to predict biological targets of miR-224-5p RESULTS: MiR-224 -5p expression was upregulated in metastatic breast cancer and non-metastatic breast cancer cells compare with control. Moreover, miR-224-5p inhibition enhanced cellular autophagy levels in breast cancer cells. MiR-224-5p could suppress Smad4 expression in MDA-MB-231 cells, which indicated that Smad4 was identified as a target of miR-224-5p in breast cancer cells with high metastatic potential CONCLUSIONS: Our study revealed that miR-224-5p inhibited autophagy by targeting Smad4 in MDA-MB-231 cells. The results indicated that miR-224-5p/Smad4 regulating autophagy might be a novel regulatory network contributing to metastasis of breast cancer. MiR-224-5p and Smad4 is involved in breast tumorigenesis, which is possibly a novel target for breast cancer therapy.

Yao Y, Luo F, Tang C, et al.
Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial.
Cancer Immunol Immunother. 2018; 67(11):1777-1788 [PubMed] Related Publications
Dendritic cell (DC)-based vaccination is a promising approach for active-specific immunotherapy, but is currently of limited efficacy. The safety and effectiveness of a DC vaccine (DCV) loaded with glioblastoma stem cell-like (GSC) antigens was assessed in glioblastoma multiforme (GBM) patients. In this double-blind, placebo-controlled phase II clinical trial, 43 GBM patients were randomized after surgery at a 1:1 ratio to receive either DCV (n = 22) or normal saline placebo (n = 21). Overall survival (OS) and progression-free survival (PFS) were analysed. Participants were stratified into different molecular subgroups based on the mutation (MT) status of isocitrate dehydrogenase (IDH1/2) and telomerase reverse transcriptase (TERT). Plasma cytokine levels, tumor-infiltrating lymphocyte numbers and immune co-inhibitory molecules PD-L1 and B7-H4 were also assessed. Multivariate Cox regression analysis revealed that DCV treatment significantly prolonged OS (p = 0.02) after adjusting for IDH1 and TERT promoter MT and B7-H4 expression, primary vs recurrent GBM. Among IDH1

Romero-Masters JC, Ohashi M, Djavadian R, et al.
An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model.
PLoS Pathog. 2018; 14(8):e1007221 [PubMed] Free Access to Full Article Related Publications
EBV causes human B-cell lymphomas and transforms B cells in vitro. EBNA3C, an EBV protein expressed in latently-infected cells, is required for EBV transformation of B cells in vitro. While EBNA3C undoubtedly plays a key role in allowing EBV to successfully infect B cells, many EBV+ lymphomas do not express this protein, suggesting that cellular mutations and/or signaling pathways may obviate the need for EBNA3C in vivo under certain conditions. EBNA3C collaborates with EBNA3A to repress expression of the CDKN2A-encoded tumor suppressors, p16 and p14, and EBNA3C-deleted EBV transforms B cells containing a p16 germline mutation in vitro. Here we have examined the phenotype of an EBNAC-deleted virus (Δ3C EBV) in a cord blood-humanized mouse model (CBH). We found that the Δ3C virus induced fewer lymphomas (occurring with a delayed onset) in comparison to the wild-type (WT) control virus, although a subset (10/26) of Δ3C-infected CBH mice eventually developed invasive diffuse large B cell lymphomas with type III latency. Both WT and Δ3C viruses induced B-cell lymphomas with restricted B-cell populations and heterogeneous T-cell infiltration. In comparison to WT-infected tumors, Δ3C-infected tumors had greatly increased p16 levels, and RNA-seq analysis revealed a decrease in E2F target gene expression. However, we found that Δ3C-infected tumors expressed c-Myc and cyclin E at similar levels compared to WT-infected tumors, allowing cells to at least partially bypass p16-mediated cell cycle inhibition. The anti-apoptotic proteins, BCL2 and IRF4, were expressed in Δ3C-infected tumors, likely helping cells avoid c-Myc-induced apoptosis. Unexpectedly, Δ3C-infected tumors had increased T-cell infiltration, increased expression of T-cell chemokines (CCL5, CCL20 and CCL22) and enhanced type I interferon response in comparison to WT tumors. Together, these results reveal that EBNA3C contributes to, but is not essential for, EBV-induced lymphomagenesis in CBH mice, and suggest potentially important immunologic roles of EBNA3C in vivo.

Dziaman T, Gackowski D, Guz J, et al.
Characteristic profiles of DNA epigenetic modifications in colon cancer and its predisposing conditions-benign adenomas and inflammatory bowel disease.
Clin Epigenetics. 2018; 10:72 [PubMed] Free Access to Full Article Related Publications
Background: Active demethylation of 5-methyl-2'-deoxycytidine (5-mdC) in DNA occurs by oxidation to 5-(hydroxymethyl)-2'-deoxycytidine (5-hmdC) and further oxidation to 5-formyl-2'-deoxycytidine (5-fdC) and 5-carboxy-2'-deoxycytidine (5-cadC), and is carried out by enzymes of the ten-eleven translocation family (TETs 1, 2, 3). Decreased level of epigenetic DNA modifications in cancer tissue may be a consequence of reduced activity/expression of TET proteins. To determine the role of epigenetic DNA modifications in colon cancer development, we analyzed their levels in normal colon and various colonic pathologies. Moreover, we determined the expressions of TETs at mRNA and protein level.The study included material from patients with inflammatory bowel disease (IBD), benign polyps (AD), and colorectal cancer (CRC). The levels of epigenetic DNA modifications and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in examined tissues were determined by means of isotope-dilution automated online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS). The expressions of
Results: IBD was characterized by the highest level of 8-oxodG among all analyzed tissues, as well as by a decrease in 5-hmdC and 5-mdC levels (at a midrange between normal colon and CRC). AD had the lowest levels of 5-hmdC and 5-mdC of all examined tissues and showed an increase in 8-oxodG and 5-(hydroxymethyl)-2'-deoxyuridine (5-hmdU) levels. CRC was characterized by lower levels of 5-hmdC and 5-mdC, the lowest level of 5-fdC among all analyzed tissues, and relatively high content of 5-cadC. The expression of
Conclusions: Our findings suggest that a complex relationship between aberrant pattern of DNA epigenetic modification and cancer development does not depend solely on the transcriptional status of TET proteins, but also on the characteristics of premalignant/malignant cells. This study showed for the first time that the examined colonic pathologies had their unique epigenetic marks, distinguishing them from each other, as well as from normal colonic tissue. A decrease in 5-fdC level may be a characteristic feature of largely undifferentiated cancer cells.

Sethi S, Sethi S, Bluth MH
Clinical Implication of MicroRNAs in Molecular Pathology: An Update for 2018.
Clin Lab Med. 2018; 38(2):237-251 [PubMed] Related Publications
MicroRNAs (miRNAs) are poised to provide diagnostic, prognostic, and therapeutic targets for several diseases including malignancies for precision medicine applications. The miRNAs have immense potential in the clinical arena because they can be detected in the blood, serum, tissues (fresh and formalin-fixed paraffin-embedded), and fine-needle aspirate specimens. The most attractive feature of miRNA-based therapy is that a single miRNA could be useful for targeting multiple genes that are deregulated in cancers, which can be further investigated through systems biology and network analysis that may provide cancer-specific personalized therapy.

Goyal G, Wong K, Nirschl CJ, et al.
PPARγ Contributes to Immunity Induced by Cancer Cell Vaccines That Secrete GM-CSF.
Cancer Immunol Res. 2018; 6(6):723-732 [PubMed] Related Publications
Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here, we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX). Mice harboring a deletion of

Li S, Yang E, Shen L, et al.
The novel truncated isoform of human manganese superoxide dismutase has a differential role in promoting metastasis of lung cancer cells.
Cell Biol Int. 2018; 42(8):1030-1040 [PubMed] Related Publications
Growing evidences have demonstrated alternative splicing makes great contribution to tumor metastasis since multiple protein isoforms from a single gene that often display different functions in the cell. Human manganese superoxide dismutase (hMnSOD) was revealed dysregulation in progress of tumor metastasis, while the effect of hMnSOD isoforms on metastasis remained unclear. In this study, we showed a novel truncated hMnSOD isoform hMnSOD183, which lacked 39 amino acids compared with hMnSOD222. We expressed two hMnSOD protein isoforms in Escherichia coli, respectively, and found that the MnSOD activity of truncated hMnSOD isoform was especially weaker. In 95-D cells, mRNA levels of hMnSOD variants and MnSOD activity were significantly increased than that in A549 cells. Furthermore, the hMnSODc exhibited lower mRNA level than hMnSODa/b in A549 and 95-D cells. Additionally, the effects of two isoforms were assessed about cell invasion, overexpression of hMnSOD222 but not hMnSOD183 promoted 95-D cells metastasis, and hMnSOD knockdown significantly reduced cells invasive behavior. Overexpression of hMnSOD isoforms also caused changes of metastasis associated proteins, such as up-regulation of MMPs, VEGF and Vimentin and down-regulation of E-cadherin. Moreover, overexpression of hMnSOD183 had weaker effect on metastasis related signaling proteins, such as Akt, JNK and IKKβ, compared to hMnSOD222. In conclusion, our study identified that hMnSOD isoforms induced lung cancer cells invasion through Akt-JNK-IKKβ signaling pathways and the hMnSOD183 isoform played a weaker role than hMnSOD222. Characterization of hMnSOD isoforms is useful for future investigation on metastasis of lung cancer cells.

Burock S, Daum S, Keilholz U, et al.
Phase II trial to investigate the safety and efficacy of orally applied niclosamide in patients with metachronous or sychronous metastases of a colorectal cancer progressing after therapy: the NIKOLO trial.
BMC Cancer. 2018; 18(1):297 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is the second most common cause of all cancer deaths in Europe and the Western world with a lifetime risk of approximately 5%. Despite several improvements in the treatment of patients with unresectable CRC prognosis is poor and there is the need of developing new treatment strategies for patients with metastatic chemorefractory disease. The S100 calcium binding protein A4 (S100A4) predicts metastasis formation and reduced CRC patient survival. S100A4 was previously identified as transcriptional target of the Wnt/β-catenin signaling pathway. The Food and Drug Administration (FDA)-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/β-catenin pathway signaling, leading to reduced expression of S100A4 linked to restricted in vivo metastasis formation. Thus, we aim at translation of our findings on restricting S100A4-driven metastasis into clinical practice for treating metastasized CRC patients progressing after standard therapy.
METHODS/DESIGN: NIKOLO is a phase II, single center, one-arm open-label clinical trial to investigate the safety and efficacy of niclosamide tablets in patients with metastasized CRC progressing under standard therapy. Eligible patients will receive 2 g of orally applied niclosamide once a day and will continue with the treatment once daily till disease progression or toxicity. Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. The primary objective of this trial is to assess the progression free survival after 4 months, secondary objectives are overall survival, time to progression, disease control rate (remission + partial remission + stable disease), and safety. Furthermore, pharmacokinetic analysis will be conducted to evaluate niclosamide plasma concentration.
DISCUSSION: This study is expected to provide evidence of the feasibility, toxicity and efficacy of niclosamide in the treatment of patients with metastasized CRC and could help to establish a new treatment option.
TRIAL REGISTRATION: The study is registered with (NCT02519582) and the European Clinical Trials Database (EudraCT 2014-005151-20).

Rahal OM, Wolfe AR, Mandal PK, et al.
Blocking Interleukin (IL)4- and IL13-Mediated Phosphorylation of STAT6 (Tyr641) Decreases M2 Polarization of Macrophages and Protects Against Macrophage-Mediated Radioresistance of Inflammatory Breast Cancer.
Int J Radiat Oncol Biol Phys. 2018; 100(4):1034-1043 [PubMed] Related Publications
PURPOSE: To determine the role of macrophage polarization on the response of inflammatory breast cancer (IBC) cells to radiation and whether modulation of macrophage plasticity can alter radiation response.
METHODS AND MATERIALS: The human THP-1 monocyte cell line and primary human monocytes isolated from peripheral blood mononuclear cells were differentiated into macrophages and polarized to either an "antitumor" (M1) or a "protumor" (M2) phenotype. These polarized macrophages were co-cultured with IBC cells (SUM149, KPL4, MDA-IBC3, or SUM190) without direct contact for 24 hours, then subjected to irradiation (0, 2, 4, or 6 Gy). Interleukin (IL)4/IL13-induced activation of STAT6 signaling was measured by Western blotting of phospho-STAT6 (Tyr641), and expression of M2 polarization gene markers (CD206, fibronectin, and CCL22) was measured by quantitative polymerase chain reaction.
RESULTS: Expression of M2 polarization markers was higher in M2-polarized macrophages after IL4/IL13 treatment than in control (M0) or M1-polarized macrophages. Co-culture of IBC cell lines with M1-polarized THP-1 macrophages mediated radiosensitivity of IBC cells, whereas co-culture with M2-polarized macrophages mediated radioresistance. Phosphopeptide mimetic PM37, targeting the SH2 domain of STAT6, prevented and reversed IL4/IL13-mediated STAT6 phosphorylation (Tyr641) and decreased the expression of M2 polarization markers. Pretreatment of M2-THP1 macrophages with PM37 reduced the radioresistance they induced in IBC cells after co-culture. Targeted proteomics analysis of IBC KPL4 cells using a kinase antibody array revealed induction of protein kinase C zeta (PRKCZ) in these cells only after co-culture with M2-THP1 macrophages, which was prevented by PM37 pretreatment. KPL4 cells with stable short hairpin RNA knockdown of PRKCZ exhibited lower radioresistance after M2-THP1 co-culture.
CONCLUSIONS: These data suggest that inhibition of M2 polarization of macrophages by PM37 can prevent radioresistance of IBC by down-regulating PRKCZ.

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.

Schulz J, Mah N, Neuenschwander M, et al.
Loss-of-function uORF mutations in human malignancies.
Sci Rep. 2018; 8(1):2395 [PubMed] Free Access to Full Article Related Publications
Ribosome profiling revealed widespread translational activity at upstream open reading frames (uORFs) and validated uORF-mediated translational control as a commonly repressive mechanism of gene expression. Translational activation of proto-oncogenes through loss-of-uORF mutations has been demonstrated, yet a systematic search for cancer-associated genetic alterations in uORFs is lacking. Here, we applied a PCR-based, multiplex identifier-tagged deep sequencing approach to screen 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes in 308 human malignancies. We identified loss-of-function uORF mutations in EPHB1 in two samples derived from breast and colon cancer, and in MAP2K6 in a sample of colon adenocarcinoma. Both mutations were associated with enhanced translation, suggesting that loss-of-uORF-mediated translational induction of the downstream main protein coding sequence may have contributed to carcinogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas subsequently revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 uORF termination codons, respectively. These data provide evidence for somatic mutations affecting uORF initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyses to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis.

Liu ZR, Sun LZ, Jia TH, Jia DF
β-Aescin shows potent antiproliferative activity in osteosarcoma cells by inducing autophagy, ROS generation and mitochondrial membrane potential loss.
J BUON. 2017 Nov-Dec; 22(6):1582-1586 [PubMed] Related Publications
PURPOSE: Osteosarcoma is one of the frequent bone tumor affecting mainly children and is associated with considerable mortality. The limited availability of anticancer drugs and less efficacious treatment options have led to poor survival rates of patients with osteosarcoma. Therefore, there is need to look for more viable treatment options and against this backdrop, natural products may prove handy. Therefore the aim of the present study was to evaluate the anticancer activity of a natural product of plant origin, β-aescin, against U2OS human osteosarcoma cells.
METHODS: U205 human osteosarcoma cell line was used in this study. Antiproliferative activity was determined by MTT assay. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were evaluated by flow cytometry. Autophagy was detected by monodansylcadaverine (MDC) staining and immunofluorescence. Protein expression was examined by western blotting.
RESULTS: The results indicated that β-aescin showed significant anticancer activity against U2OS human osteosarcoma cells and exhibited an IC50 of 40 μM. β-aescin treatment caused significant increase in ROS and decrease in the MMP. The anticancer effect of β-aescin was found to be due mainly to autophagic cell death as evidenced from MDC staining and immunofluorescence. Moreover, β-aescin caused significant increase in the expression levels of LC3- II protein in U2OS osteosarcoma cells in a time and dosedependent manner.
CONCLUSION: Taken together we propose that β-aescin may prove a lead molecule in the management of osteosarcoma and deserves further research efforts.

Liu F, Gao S, Yang Y, et al.
Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway.
Oncol Rep. 2018; 39(3):1523-1531 [PubMed] Related Publications
Curcumin is known to exhibit anticancer effects on various cancers with selective cytotoxicity in tumor cells. In the present study, the effects of curcumin‑induced multiple PCDs on human non‑small cell lung cancer (NSCLC) cells and the potential molecular mechanisms of apoptosis and autophagy triggered by curcumin via the PI3K/Akt/mTOR signaling pathway were explored, further confirmed by co‑culture of curcumin with mTOR blocker rapamycin and PI3K/Akt inhibitor LY294002. The anti‑proliferation effect of different stimulus was measured by MTT assay. Apoptosis was detected by flow cytometry. Autophagy induction was detected by MDC labeling and western blotting of Beclin1, LC3, and p62 expression. The mRNA and protein expression levels of Akt and mTOR were assayed by real‑time fluorescence quantitative (qRT‑PCR) technique and western blotting. Our results showed that curcumin inhibited the viability of A549 cells time‑ and dose‑dependently. In addition, a dosage-dependent A549 cell apoptosis‑induction phenomena was observed by the curcumin intervention. Moreover, obvious autophagy was induced after curcumin‑treatment, characterized by the formation of fluorescent particles [autophagic vesicles (AVs)] and significant increase in ratio of LC3‑Ⅱ/LC3‑Ⅰ and Beclin1 as well as decreased p62 expression. Furthermore, the effect of curcumin on a substantial downregulation of phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was observed. It is worth noting that the inhibition of mTOR by rapamycin or of PI3K/Akt by LY294002 augmented curcumin‑induced apoptosis and autophagy, leading to significant inhibition of cell proliferation. From these findings, it can be speculated that curcumin potently inhibit the cell growth of NSCLC A549 cells through inducing both apoptosis and autophagy by inhibition of the PI3K/Akt/mTOR pathway. These results support the potential use of curcumin as a novel candidate in treatment of human lung cancer.

Schubert M, Klinger B, Klünemann M, et al.
Perturbation-response genes reveal signaling footprints in cancer gene expression.
Nat Commun. 2018; 9(1):20 [PubMed] Free Access to Full Article Related Publications
Aberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions. Here we present PROGENy, a method that overcomes both limitations by leveraging a large compendium of publicly available perturbation experiments to yield a common core of Pathway RespOnsive GENes. Unlike pathway mapping methods, PROGENy can (i) recover the effect of known driver mutations, (ii) provide or improve strong markers for drug indications, and (iii) distinguish between oncogenic and tumor suppressor pathways for patient survival. Collectively, these results show that PROGENy accurately infers pathway activity from gene expression in a wide range of conditions.

Zhang C, Li P, Zhang S, et al.
Oxidative stress-elicited autophagosome accumulation contributes to human neuroblastoma SH-SY5Y cell death induced by PBDE-47.
Environ Toxicol Pharmacol. 2017; 56:322-328 [PubMed] Related Publications
Polybrominated diphenyl ethers, a ubiquitous persistent organic pollutant used as brominated flame retardants, is known to damage nervous system, however the underlying mechanism is still elusive. In this study, we used human neuroblastoma SH-SY5Y cells to explore the effects of PBDE-47 on autophagy and investigate the role of autophagy in PBDE-47-induced cell death. Results showed PBDE-47 could increase autophagic level (performation of cell ultrastructure with double membrane formation, MDC-positive cells raised, autophagy-related proteins LC3-II, Beclin1 and P62 increased) after cells exposed to PBDE-47. Then cells were exposed to PBDE-47 (1, 5, 10μmol/L) respectively for 1, 3, 6, 9, 12, 18, 24h, and the results showed that PBDE-47 increased the levels of LC3-II, Beclin1 and P62 in 5, 10μmol/L (9, 12, 18, 24h) PBDE-47 exposed groups. Furthermore, ROS scavenger N-Acetyl-l-cysteine (NAC), autophagic inhibitor 3-methyladenine (3-MA) and 5μmol/L PBDE-47 treated for 9h and 24h were chosen for the follow-up research. Moreover, 3-MA significantly improved cell viability when cells exposed to 5 and 10μmol/L PBDE-47, indicating that PBDE-47-induced autophagic cell death. Importantly, NAC could decrease PBDE-47-induced LC3-II, Beclin1 and P62 expression. We concluded that autophagosome accumulation mediated by oxidative stress may contribute to SH-SY5Y cell death induced by PBDE-47.

Giardino A, Innamorati G, Ugel S, et al.
Immunomodulation after radiofrequency ablation of locally advanced pancreatic cancer by monitoring the immune response in 10 patients.
Pancreatology. 2017 Nov - Dec; 17(6):962-966 [PubMed] Related Publications
OBJECTIVE/BACKGROUND: RFA of pancreatic cancer has been demonstrated to be feasible and safe with a positive impact on survival. The aim was to investigate whether an immune reaction is activated after locally advanced pancreatic cancer (LAPC) ablation.
METHODS: Peripheral Blood samples were obtained preoperatively and on post-operative days 3-30. Evaluated parameters were: cells [CD4
RESULTS: Ten patients were enrolled. CD4
CONCLUSIONS: This study provides the first evidence of RFA-based immunomodulation in LAPC. We observed a general activation of adaptive response along with a decrease of immunosuppression. Furthermore, most cells showed prolonged activation some weeks after the procedure, suggesting true immunomodulation rather than a normal inflammatory response.

Aleksandrova K, Jenab M, Leitzmann M, et al.
Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC cohort.
Int J Epidemiol. 2017; 46(6):1823-1835 [PubMed] Free Access to Full Article Related Publications
Background: There is convincing evidence that high physical activity lowers the risk of colon cancer; however, the underlying biological mechanisms remain largely unknown. We aimed to determine the extent to which body fatness and biomarkers of various biologically plausible pathways account for the association between physical activity and colon cancer.
Methods: We conducted a nested case-control study in a cohort of 519 978 men and women aged 25 to 70 years followed from 1992 to 2003. A total of 713 incident colon cancer cases were matched, using risk-set sampling, to 713 controls on age, sex, study centre, fasting status and hormonal therapy use. The amount of total physical activity during the past year was expressed in metabolic equivalent of task [MET]-h/week. Anthropometric measurements and blood samples were collected at study baseline.
Results: High physical activity was associated with a lower risk of colon cancer: relative risk ≥91 MET-h/week vs <91 MET-h/week = 0.75 [95% confidence interval (CI): 0.57 to 0.96]. In mediation analyses, this association was accounted for by waist circumference: proportion explained effect (PEE) = 17%; CI: 4% to 52%; and the biomarkers soluble leptin receptor (sOB-R): PEE = 15%; 95% CI: 1% to 50% and 5-hydroxyvitamin D (25[OH]D): PEE = 30%; 95% CI: 12% to 88%. In combination, these factors explained 45% (95% CI: 20% to 125%) of the association. Beyond waist circumference, sOB-R and 25[OH]D additionally explained 10% (95% CI: 1%; 56%) and 23% (95% CI: 6%; 111%) of the association, respectively.
Conclusions: Promoting physical activity, particularly outdoors, and maintaining metabolic health and adequate vitamin D levels could represent a promising strategy for colon cancer prevention.

Omland SH, Wettergren EE, Mollerup S, et al.
Cancer associated fibroblasts (CAFs) are activated in cutaneous basal cell carcinoma and in the peritumoural skin.
BMC Cancer. 2017; 17(1):675 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cutaneous basal cell carcinoma (BCC) is the commonest cancer worldwide. BCC is locally invasive and the surrounding stromal microenvironment is pivotal for tumourigenesis. Cancer associated fibroblasts (CAFs) in the microenvironment are essential for tumour growth in a variety of neoplasms but their role in BCC is poorly understood.
METHODS: Material included facial BCC and control skin from the peritumoural area and from the buttocks. With next-generation sequencing (NGS) we compared mRNA expression between BCC and peritumoural skin. qRT-PCR, immunohistochemical and immunofluorescent staining were performed to validate the NGS results and to investigate CAF-related cyto-and chemokines.
RESULTS: NGS revealed upregulation of 65 genes in BCC coding for extracellular matrix components pointing at CAF-related matrix remodeling. qRT-PCR showed increased mRNA expression of CAF markers FAP-α, PDGFR-β and prolyl-4-hydroxylase in BCC. Peritumoural skin (but not buttock skin) also exhibited high expression of PDGFR-β and prolyl-4-hydroxylase but not FAP-α. We found a similar pattern for the CAF-associated chemokines CCL17, CCL18, CCL22, CCL25, CXCL12 and IL6 with high expression in BCC and peritumoural skin but absence in buttock skin. Immunofluorescence revealed correlation between FAP-α and PDGFR-β and CXCL12 and CCL17.
CONCLUSION: Matrix remodeling is the most prominent molecular feature of BCC. CAFs are present within BCC stroma and associated with increased expression of chemokines involved in tumour progression and immunosuppression (CXCL12, CCL17). Fibroblasts from chronically sun-exposed skin near tumours show gene expression patterns resembling that of CAFs, indicating that stromal fibroblasts in cancer-free surgical BCC margins exhibit a tumour promoting phenotype.

Rodríguez-Ubreva J, Català-Moll F, Obermajer N, et al.
Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells.
Cell Rep. 2017; 21(1):154-167 [PubMed] Related Publications
Myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs) arise from common progenitors. Tumor-derived factors redirect differentiation from immune-promoting DCs to tolerogenic MDSCs, an immunological hallmark of cancer. Indeed, in vitro differentiation of DCs from human primary monocytes results in the generation of MDSCs under tumor-associated conditions (PGE2 or tumor cell-conditioned media). Comparison of MDSC and DC DNA methylomes now reveals extensive demethylation with specific gains of DNA methylation and repression of immunogenic-associated genes occurring in MDSCs specifically, concomitant with increased DNA methyltransferase 3A (DNMT3A) levels. DNMT3A downregulation erases MDSC-specific hypermethylation, and it abolishes their immunosuppressive capacity. Primary MDSCs isolated from ovarian cancer patients display a similar hypermethylation signature in connection with PGE2-dependent DNMT3A overexpression. Our study links PGE2- and DNMT3A-dependent hypermethylation with immunosuppressive MDSC functions, providing a promising target for therapeutic intervention.

Omland SH
Local immune response in cutaneous basal cell carcinoma.
Dan Med J. 2017; 64(10) [PubMed] Related Publications
BCC is an immunogenic tumor highlighted by the increased risk in immunosuppressed individuals and the frequent occurrence of tumor infiltrating lymphocytes (TILs) in the tumor surroundings. Immunotherapy is evolving as a promising treatment strategy for several cancer types where topical immunostimulators are among the possibilities for superficial BCC. The overall aim of this thesis is to characterize the immunologic response upon BCC as well as characterizing the surrounding tumor stroma. The aim was achieved by the use of a variety of laboratory techniques; immunohistochemistry, immunoflourescence, qRT-PCR and NGS. Tumor microenvironment: T-regs are a subpopulation of the CD4 positive T-cells normally comprising around 5-10% of the peripheral T-cells and up to 20% of the skin resident T-cells. In the healthy individual they are crucial in hindering autoimmune diseases whereas the role in cancer is less advantageous with association to tumor progression for a variety of cancer types. By investigating the presence of T-regs in BCC by immunohistochemistry in study I, it was found that T-regs comprised 45% in mean of the total CD4 positive cells in BCC. The increased T-reg concentration was confirmed with qRT-PCR showing increased Foxp3 expression levels in BCC as well as in the peritumoral skin. In the normal non-UV exposed buttock skin, no Foxp3 expression was found. Hence, T-regs seem to play a role both in BCC but also in the tumor surroundings. Tumor surroundings are essential in terms of the ability for a tumor to grow. Apart from interaction between immune and cancer cells, also crosstalk with cells of the connective tissue such as CAFs is essential. In study II, NGS revealed increased expression of the CAF-markers P4H and PDGFR-β in BCC. Subsequent qRT-PCR confirmed this and also showed increased expression in the peritumoral skin whereas no expression was found in the normal buttock skin. FAP-α expression was seen only within BCC. CAFs are thus highly present within BCC and we further hypothesize that fibroblasts in the peritumoral skin acquire a phenotype intermediate between normal fibroblasts and CAFs in BCC. This intermediate phenotype might be induced by chronic UV-exposure mediated by increased IL6 expression. This corresponds to our findings of highly increased IL6 expression primarily in the peritumoral skin and to previous literature describing CAF-induced tumor-promoting IL6 expression upon UV-exposure in cutaneous SCC. Recruitment of TILs to BCC: mRNA expression levels of the chemokines CCL17, CCL18, CCL22 and CXCL12, involved in T-reg attraction to tumor sites were increased both in tumor and peritumoral skin with lack of expression in the normal skin. Correlation between the chemokines CCL17 and CXCL12 and CAF markers was found by IF establishing a role for CAFs in attracting T-regs to tumor sites. Efficient immunologic anti-tumor response could be provided by clonal expansion of T-cells directed against tumor-antigens. If this was the case, then restricted TCR-repertoire in BCC compared with surrounding skin would be seen. Analysis of the α and β- chain of the TCR was performed showing a high diversity of TCR repertoire in BCC and lack of predominant V(D)J-gene usage, no preferential VJ pairing or specific CDR3 length distribution. Therefore, no support of antigen-driven clone selection was found. This corresponds with lack of obvious anti-tumor skewing towards a Th1, Th2 or Th17 polarization.
CONCLUSION: To summarize it has been shown, with these studies on the local immune response upon BCC development, that an immunologic response is generated in line with BCC being an immunogenic tumor. This response is not specific, though. Additionally, BCC is capable of generating a protective niche in the microenvironment composed of both T-regs and CAFs breeding local immunosuppression and hindering of adequate anti-tumor response. In a clinical perspective, further research in improving immunotherapy for BCC is promising since an immunological response is present but needs to be reactivated.

Kebriaei P, Izsvák Z, Narayanavari SA, et al.
Gene Therapy with the Sleeping Beauty Transposon System.
Trends Genet. 2017; 33(11):852-870 [PubMed] Related Publications
The widespread clinical implementation of gene therapy requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective, and economical manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient nonviral gene delivery approaches that are prevalent in ongoing clinical trials. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here, we review the most important aspects of using SB for gene therapy, including vectorization as well as genomic integration features. We also illustrate the path to successful clinical implementation by highlighting the application of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy.

Cohen M, Vistarop AG, Huaman F, et al.
Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact.
Sci Rep. 2017; 7(1):10813 [PubMed] Free Access to Full Article Related Publications
Epstein-Barr Virus (EBV) is present in neoplastic cells of 15% of Asian and Latin-American diffuse large B-cell lymphoma (DLBCL) patients. Even though a tolerogenic microenvironment was recently described in DLBCL, little is known concerning immunomodulatory features induced by EBV. As suggested in Hodgkin lymphoma, EBV-specific cytotoxic T-cells are increased but showing immune exhaustion features. Hence, host immunity suppression may play a critical role in tumor progression. This study aimed to investigate, whether an association between tumor microenvironment features and EBV presence is taking place, and its clinical correlate. The incidence of EBV+DLBCL NOS was 12.6% in this cohort. Cytokine and chemokine transcripts expression and immunophenotype analysis showed that EBV infection was associated with increased gene expression of immunosuppressive cytokine (IL-10) together with increased CD8+ T-cells and granzyme B+ cytotoxic effector cells. However, this specific response coexists with a tolerogenic milieu, by PD-1 expression, in EBV+ and EBV-DLBCL cases. High PD-1+ cell counts, EBV presence and low CCL22 expression were associated with worse survival, supporting our hypothesis that EBV-specific response is mounted locally and its inhibition by, for example PD-1+ cells, may negatively affect outcome. The better understanding of the interplay between lymphoma cells and microenvironment in a viral framework could thereby facilitate the discovery of new targets for innovative anti-lymphoma treatment strategies.

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