Research IndicatorsGraph generated 16 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 16 March, 2017 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CD83 (cancer-related)
Zhou J, Ma P, Li J, et al.Improvement of the cytotoxic T lymphocyte response against hepatocellular carcinoma by transduction of cancer cells with an adeno-associated virus carrying the interferon-γ gene.
Mol Med Rep. 2016; 13(4):3197-205 [PubMed
] Related Publications
Dendritic cell (DC)-based antigen-targeted immunotherapy may offer effective adjuvant therapy for hepatocellular carcinoma (HCC), in which cytotoxic T lymphocytes (CTLs) are key. However, in a number of cases, the activity of CTLs is completely inhibited due to the downregulated expression of major human leukocyte antigen (HLA) class I molecules by HCC cells. The aim of the present study was to overcome this issue. Hep3B cells were transduced by HCC‑specific recombinant adeno‑associated virus (rAAV) carrying human α‑fetoprotein promoter (AFPp) and the interferon‑γ (IFN‑γ) gene (rAAV/AFPp‑IFN‑γ). rAAV carrying the cytomegalovirus promoter (CMVp) and human α‑fetoprotein (AFP) gene (rAAV/CMVp‑AFP) was used to transduce professional antigen‑presenting DCs for the purpose of stimulating a CTL response. It was observed that transduction of DCs with rAAV/CMVp‑AFP resulted in: (i) AFP and interleukin‑12 expression; (ii) high expression levels of cluster of differentiation (CD)80, CD83, CD86, CD40, HLA‑death receptor and CD1a; (iii) T cell populations with marked IFN‑γ expression; (iv) a high percentage of CD69+/CD8+ T cells; and (v) the activity of CTLs against HLA‑A2‑expressing Hep3B cells. The transduction of Hep3B cells with rAAV/AFPp‑IFN‑γ resulted in: (i) IFN‑γ expression; (ii) upregulated expression of HLA‑A2; and (iii) an improved CTL response against HLA‑A2‑deficient Hep3B cells. rAAV/CMVp‑AFP‑transduced DCs elicited an AFP‑specific and HLA‑class I‑restricted CTL response against Hep3B cells. In conclusion, it was shown that the transduction of Hep3B with rAAV/AFPp-IFN-γ upregulated the expression of HLA-A2 and improved the sensitivity to CTL response.
Bock S, Murgueitio MS, Wolber G, Weindl GAcute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement.
Pharmacol Res. 2016; 105:44-53 [PubMed
] Related Publications
Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, co-culture with naive CD4(+) T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.
Meng FD, Wang S, Jiang YH, Sui CGAntitumor effect of dendritic cells transfected with prostate-specific membrane antigen recombinant adenovirus on prostate cancer: An in vitro study.
Mol Med Rep. 2016; 13(3):2124-34 [PubMed
] Related Publications
The aim of the present study was to construct a dendritic cell (DC) vaccine transfected with a prostate-specific membrane antigen (PSMA) recombinant adenovirus and to observe the ability of the recombinant DCs in eliciting a PSMA-directed T‑cell response to prostate cancer (PCa) in vitro. Replication‑defective adenoviral vectors, were constructed using the Adxsi system. The virus titer was measured by TCID50 assay, and the expression of the PSMA gene was identified by polymerase chain reaction (PCR) generation of peripheral blood mononuclear cell (PBMC) derived DCs in vitro. In addition, a PE‑7AAD apoptosis and necrosis kit was applied to detect the survival of DCs at different MOI values to determine the optimal MOI. Morphological changes of DC were observed under a fluorescence microscope, expression of the PSMA protein was detected by western blotting 48 h after transfection, the expression of DC markers prior to and following transfection was detected by direct immunofluorescence, and the interleukin (IL)-12 concentration in the culture supernatant of the three groups was measured by ELISA. The antitumor effect of DC-stimulated cytotoxic T lymphocytes (CTLs) on different PCa cell lines was analyzed using a Cell Counting Kit‑8 assay. The optimal MOI value was determined to be 200. The PSMA protein was expressed in DCs, and the recombinant adenovirus did not impact the maturation and morphological changes of the DCs. The expression levels of the co-stimulatory molecules, CD80, CD83, CD86 and HLA‑DR, were significantly higher in the Ad‑PSMA‑DC group than in the other two groups (P<0.05). The concentration of IL‑12 in the supernatant of the Ad‑PSMA‑DC group (79.51±1.60 pg) was comparable with that of the Ad‑GFP‑DC group (not significantly different), and the two were significantly higher than the non‑transfection group (P<0.05). The optimal effector to target (E:T) ratio was determined to be 40:1. However, at the same E:T ratio, the cytotoxic activity of PSMA‑DC‑T against the LNCap cells was markedly stronger than its activity against the other target cells (DU145 and 22RV; P<0.05); furthermore, the the cytotoxic activity of PSMA-DC-T against the LNCap cells was significantly higher than the anti‑LNCap effect of DC‑T cells in other groups (P<0.05). In vitro experiments indicated that mature DCs transfected with Ad‑PSMA secreted high concentrations of IL‑12 and elicited potent antitumor immune responses targeting PSMA‑expressing cells by stimulating the cytotoxic activity of CTLs.
Telomeric repeat-containing RNA (TERRA) has been identified as a telomere-associated regulator of chromosome end protection. Here, we report that TERRA can also be found in extracellular fractions that stimulate innate immune signaling. We identified extracellular forms of TERRA in mouse tumor and embryonic brain tissue, as well as in human tissue culture cell lines using RNA in situ hybridization. RNA-seq analyses revealed TERRA to be among the most highly represented transcripts in extracellular fractions derived from both normal and cancer patient blood plasma. Cell-free TERRA (cfTERRA) could be isolated from the exosome fractions derived from human lymphoblastoid cell line (LCL) culture media. cfTERRA is a shorter form (∼200 nt) of cellular TERRA and copurifies with CD63- and CD83-positive exosome vesicles that could be visualized by cyro-electron microscopy. These fractions were also enriched for histone proteins that physically associate with TERRA in extracellular ChIP assays. Incubation of cfTERRA-containing exosomes with peripheral blood mononuclear cells stimulated transcription of several inflammatory cytokine genes, including TNFα, IL6, and C-X-C chemokine 10 (CXCL10) Exosomes engineered with elevated TERRA or liposomes with synthetic TERRA further stimulated inflammatory cytokines, suggesting that exosome-associated TERRA augments innate immune signaling. These findings imply a previously unidentified extrinsic function for TERRA and a mechanism of communication between telomeres and innate immune signals in tissue and tumor microenvironments.
BACKGROUND: Theoretically human embryonic stem cells (hESCs) have the capacity to self-renew and differentiate into all human cell types. Therefore, the greatest promise of hESCs-based therapy is to replace the damaged tissues of patients suffering from traumatic or degenerative diseases by the exact same type of cells derived from hESCs. Allograft immune rejection is one of the obstacles for hESCs-based clinical applications. Human leukocyte antigen (HLA) II leads to CD4(+) T cells-mediated allograft rejection. Hence, we focus on optimizing hESCs for clinic application through gene modification.
RESULTS: Transcription activator-like effector nucleases (TALENs) were used to target MHC class II transactivator (CIITA) in hESCs efficiently. CIITA (-/-) hESCs did not show any difference in the differentiation potential and self-renewal capacity. Dendritic cells (DCs) derived from CIITA (-/-) hESCs expressed CD83 and CD86 but without the constitutive HLA II. Fibroblasts derived from CIITA (-/-) hESCs were powerless in IFN-γ inducible expression of HLA II.
CONCLUSION: We generated HLA II defected hESCs via deleting CIITA, a master regulator of constitutive and IFN-γ inducible expression of HLA II genes. CIITA (-/-) hESCs can differentiate into tissue cells with non-HLA II expression. It's promising that CIITA (-/-) hESCs-derived cells could be used in cell therapy (e.g., T cells and DCs) and escape the attack of receptors' CD4(+) T cells, which are the main effector cells of cellular immunity in allograft.
To explore the mechanisms of MDSC trafficking and accumulation during tumor progression. In this study, we report significant CD40 upregulation in tumor-infiltrating MDSC when compared with splenic MDSC. Microarray analyses comparing CD40(high) and CD40l(ow) MDSC revealed 1872 differentially expressed genes, including CD83, CXCR5, BTLA, CXCL9, TLR1, FLT3, NOD2 and CXCL10. In vivo experiments comparing wild-type (WT) and CD40 knockout (KO) mice demonstrated that CD40 critically regulates CXCR5 expression. Consistently, the transwell analysis confirmed the essential role of CXCR5-CXCL13 crosstalk in the migration of CD40+ MDSC toward gastric cancer. Furthermore, more MDSC accumulated in the gastric cancers of WT mice when compared with KO mice, and the WT tumors mostly contained CD40+ cells. Functionally, tumors grew faster in WT than KO mice. In conclusion, we demonstrate that CD40 expression upregulates the chemokine receptor CXCR5 and promotes MDSC migration toward and accumulation within cancer. Therefore, this study provides preliminary evidence that CD40 may stimulate tumor growth by enabling immune evasion via MDSC recruitment and inhibition of T cell expansion.
Riley CH, Brimnes MK, Hansen M, et al.Interferon-α induces marked alterations in circulating regulatory T cells, NK cell subsets, and dendritic cells in patients with JAK2V617F-positive essential thrombocythemia and polycythemia vera.
Eur J Haematol. 2016; 97(1):83-92 [PubMed
] Related Publications
Long-term therapy with IFN-α2 is associated with sustained major molecular remissions in JAK2-positive ET and PV. The efficacy of IFN-α2 may be partly mediated by modulation of immune cells, which was investigated in twenty patients with ET (n = 6) and PV (n = 14). The frequency of CD4(+) CD25(+) Foxp3(+) T cells was significantly increased during IFN-α2 treatment in all patients (P < 0.0001). A significant expansion of the CD56(bright) NK cells (P = 0.0002) and a concomitant decrease in the frequency of CD56(dim) NK cells (P < 0.0001) were also detected. Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were studied in nine patients, and decreased frequencies of both cell types were observed during the course of treatment. On both mDCs and pDCs, HLA-ABC expression was upregulated (P = 0.003), but decreasing expression levels of HLA-DR was detected on mDCs. The expression of CD40 (P = 0.002), CD83 (P = 0.03), and CD86 (P = 0.01) increased, but was confined to pDCs. Furthermore, PD-L1 expression was reduced on mDC (P = 0.003) and increased on pDCs (P = 0.02). No significant correlations were found between the changes in immune cells and hematological or molecular responses achieved in our cohort of patients. So forth, it remains to be revealed whether the profound changes in circulating immune cells contribute to the beneficial effects of long-term IFN-α2 treatment in some patients.
Schneider MA, Granzow M, Warth A, et al.Glycodelin: A New Biomarker with Immunomodulatory Functions in Non-Small Cell Lung Cancer.
Clin Cancer Res. 2015; 21(15):3529-40 [PubMed
] Related Publications
PURPOSE: In recent years, immune therapeutic strategies against non-small cell lung cancer (NSCLC) based on tissue-derived biomarkers, for example PD1/PD-L1 (CD274), have evolved as novel and promising treatment options. However, the crosstalk between tumor and immune cells is poorly understood. Glycodelin (gene name PAEP), initially described in the context of pregnancy and trophoblastic implantation, is a secreted immunosuppressive glycoprotein with an as-of-yet largely unknown function in lung cancer.
EXPERIMENTAL DESIGN: In this study, we characterized the expression and role of glycodelin in NSCLC through mRNA and protein expression analyses, functional knockdown experiments, and correlations with clinicopathologic parameters.
RESULTS: Glycodelin mRNA expression was significantly elevated in tumors (n = 336) compared with matched normal tissue (P < 0.0001). Overall survival (OS) was significantly reduced in NSCLC with high glycodelin mRNA levels in women but not in men. Glycodelin was detected in the sera of patients, and the levels correlated with recurrence and metastatic disease. Knockdown of glycodelin with siRNAs in NSCLC cell lines resulted in significant upregulation of immune system modulatory factors such as PDL1, CXCL5, CXCL16, MICA/B, and CD83 as well as proliferation stimulators EDN1 and HBEGF. Furthermore, decreased migration of tumor cells was observed.
CONCLUSIONS: Altogether, the comprehensive characterization of glycodelin in NSCLC provides strong support for its use as a biomarker with immune modulatory function.
Turbica I, Gallais Y, Gueguen C, et al.Ectosomes from neutrophil-like cells down-regulate nickel-induced dendritic cell maturation and promote Th2 polarization.
J Leukoc Biol. 2015; 97(4):737-49 [PubMed
] Related Publications
DCs are the first immune cells to be exposed to allergens, including chemical sensitizers, such as nickel, a human TLR4 agonist that induces DC maturation. In ACD, DCs can interact with PMNs that are recruited and activated, leading, in particular, to ectosome release. The objective of this work was to characterize the effects of PMN-Ect on DC functions in an ACD context. We first developed a standardized protocol to produce, characterize, and quantify ectosomes by use of human PLB-985 cells, differentiated into mature PMN (PLB-Ect). We then studied the in vitro effects of these purified ectosomes on human moDC functions in response to NiSO4 and to LPS, another TLR4 agonist. Confocal fluorescence microscopy showed that PLB-Ect was internalized by moDCs and localized in the lysosomal compartment. We then showed that PLB-Ect down-regulated NiSO4-induced moDC maturation, as witnessed by decreased expression of CD40, CD80, CD83, CD86, PDL-1, and HLA-DR and by decreased levels of IL-1β, IL-6, TNF-α, and IL-12p40 mRNAs. These effects were related to p38MAPK and NF-κB down-regulation. However, no increase in pan-regulatory DC marker genes (GILZ, CATC, C1QA) was observed; rather, levels of effector DC markers (Mx1, NMES1) were increased. Finally, when these PLB-Ect + NiSO4-treated moDCs were cocultured with CD4(+) T cells, a Th2 cytokine profile seemed to be induced, as shown, in particular, by enhanced IL-13 production. Together, these results suggest that the PMN-Ect can modulate DC maturation in response to nickel, a common chemical sensitizer responsible for ADC.
Théate I, van Baren N, Pilotte L, et al.Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues.
Cancer Immunol Res. 2015; 3(2):161-72 [PubMed
] Related Publications
Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tumoral resistance to immune rejection. In humans, constitutive expression of IDO1 has been observed in several tumor types. However, a comprehensive analysis of its expression in normal and tumor tissues is still required to anticipate the risks and potential benefits of IDO1 inhibitors. Using a newly validated monoclonal antibody to human IDO1, we performed an extensive immunohistochemical analysis of IDO1 expression in normal and tumor tissues. In normal tissues, IDO1 was expressed by endothelial cells in the placenta and lung and by epithelial cells in the female genital tract. In lymphoid tissues, IDO1 was expressed in mature dendritic cells with a phenotype (CD83(+), DC-LAMP(+), langerin(-), CD123(-), CD163(-)) distinct from plasmacytoid dendritic cells. Importantly, IDO1-expressing dendritic cells were not enriched in tumor-draining lymph nodes, in contrast with previously reported findings. IDO1-expressing cells were observed in a large fraction (505/866, 58%) of human tumors. They comprised tumor cells, endothelial cells, and stromal cells in proportions that varied depending on the tumor type. Tumors showing the highest proportions of IDO1-immunolabeled samples were carcinomas of the endometrium and cervix, followed by kidney, lung, and colon. This hierarchy of IDO1 expression was confirmed by gene expression data mined from The Cancer Genome Atlas database. Expression of IDO1 may be used to select tumors likely to benefit from targeted therapy with IDO1 inhibitors.
Yang YF, Xue SY, Lu ZZ, et al.Antitumor effects of oncolytic adenovirus armed with PSA-IZ-CD40L fusion gene against prostate cancer.
Gene Ther. 2014; 21(8):723-31 [PubMed
] Related Publications
Advanced prostate cancer (PC) still remains incurable. Novel immunogene therapy shows promise as treatment strategy that can target both localized and metastasized PC. In this study, we have developed a PC-specific oncolytic adenovirus (Ad-PL-PPT-E1A) armed with fusion gene of prostate-specific antigen and CD40 ligand, and aimed to evaluate its therapeutic effect in vitro and in vivo. After they were rescued in human embryonic kidney 293 cells, we confirmed that Ad-PL-PPT-E1A could mediate the expression of E1A efficiently and produce abundant progeny viruses in PC cells in vitro. Our data showed that Ad-PL-PPT-E1A induced apoptosis and resulted in specific oncolytic toxicity in PC cells, which was detected by Annexin-V staining and crystal violet, respectively. After stimulation with lysates, immune phenotypes and cytokines expression of human dendritic cells was detected by flow cytometry and real-time polymerase chain reaction, respectively. And, the results showed that the lysate of Ad-PL-PPT-E1A-infected LNCaP cells upregulated the expression of CD80, CD83, CD86 and mRNA level of interleukin-6 (IL-6), IL-12, IL-23 and tumor necrosis factor-α significantly. In established PC3M cell-xenografted mouse models, Ad-PL-PPT-E1A treatment improved the survival and suppressed the tumor growth obviously. In conclusion, Ad-PL-PPT-E1A exhibited enhanced antitumor activity is a promising approach for gene therapy of advanced PC.
Antigen-specific T cells provide a therapy for cancer that is highly specific, self-replicating, and potentially devoid of toxicity. Ideally, tumor-specific T cells should recognize multiple epitopes on multiple antigens to prevent tumor immune escape. However the large-scale expansion of such broad-spectrum T cells has been limited by the availability of potent autologous antigen-presenting cells that can present antigens on the polymorphic array of each patient's HLA allotype. We evaluated a novel antigen-presenting complex (KATpx) in which antigens in the form of peptide libraries can be presented by autologous activated T cells, whereas costimulation is complemented in trans by an HLA-negative K562 cell line genetically modified to express CD80, CD83, CD86, and 4-1BBL (K562cs). The additional costimulation provided by K562cs significantly enhanced T-cell expansion in culture over autologous activated T cells alone while maintaining antigen specificity. We validated this antigen-presenting system by generating Epstein-Barr virus (EBV) antigen-specific T cells from healthy donors and from patients with EBV-positive malignancies including nasopharyngeal carcinoma and multiply relapsed EBV-positive lymphoma. These T cells were specific for EBNA1, LMP1, and LMP2, the viral antigens expressed in these type 2 latency EBV-associated malignancies. The KATpx system consistently activated and expanded antigen-specific T cells both from healthy donors and from 5 of 6 patients with lymphoma and 6 of 6 with nasopharyngeal carcinoma, while simplifying the process for generating APCs by eliminating the need for live virus (EBV) or viral vectors to force expression of transgenic EBV antigens. Hence, KATpx provides a robust, reliable, and scalable process to expand tumor-directed T cells for the treatment of virus-associated cancers.
Döring C, Hansmann ML, Agostinelli C, et al.A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma.
Mod Pathol. 2014; 27(10):1345-54 [PubMed
] Related Publications
Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.
Ahmed Ali HA, Di J, Mei W, et al.Antitumor activity of lentivirus-mediated interleukin -12 gene modified dendritic cells in human lung cancer in vitro.
Asian Pac J Cancer Prev. 2014; 15(2):611-6 [PubMed
] Related Publications
OBJECTIVES: Dendritic cell (DC)-based tumor immunotherapy needs an immunogenic tumor associated antigen (TAA) and an effective approach for its presentation to lymphocytes. In this study we explored whether transduction of DCs with lentiviruses (LVs) expressing the human interleukin-12 gene could stimulate antigen- specific cytotoxic T cells (CTLs) against human lung cancer cells in vitro.
METHODS: Peripheral blood monocyte- derived DCs were transduced with a lentiviral vector encoding human IL-12 gene (LV-12). The anticipated target of the human IL-12 gene was detected by RT-PCR. The concentration of IL-12 in the culture supernatant of DCs was measured by ELISA.Transduction efficiencies and CD83 phenotypes of DCs were assessed by flow cytometry. DCs were pulsed with tumor antigen of lung cancer cells (DC+Ag) and transduced with LV-12 (DC-LV-12+Ag). Stimulation of T lymphocyte proliferation by DCs and activation of cytotoxic T-lymphocytes (CTL) stimulated by LV-12 transduced DCs pulsed with tumor antigen against A549 lung cancer cells were assessed with methyl thiazolyltetrazolium (MTT).
RESULTS: A recombinant lentivirus expressing the IL-12 gene was successfully constructed. DC transduced with LV-12 produced higher levels of IL-12 and expressed higher levels of CD83 than non-transduced. The DC modified by interleukin -12 gene and pulsed with tumor antigen demonstrated good stimulation of lymphocyte proliferation, induction of antigen-specific cytotoxic T lymphocytes and anti- tumor effects.
CONCLUSIONS: Dendritic cells transduced with a lentivirus-mediated interleukin-12 gene have an enhanced ability to kill lung cancer cells through promoting T lymphocyte proliferation and cytotoxicity.
Tocotrienol-rich fraction (TRF) from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC)-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL) from 4T1 cells (DC+TL) once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF) inhibited (p<0.05) tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC)-treated 4T1 cells produced higher (p<0.05) levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL) assay also showed enhanced tumor-specific killing (p<0.05) by CD8(+) T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.
Gulubova M, Manolova I, Ananiev J, et al.Relationship of TGF-β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis.
APMIS. 2013; 121(10):967-75 [PubMed
] Related Publications
Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF-β1 expression in tumor cell cytoplasm correlated with low CD1a(+) and low CD83(+) DCs infiltration. The tissue levels of TGF-β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two-color FACS analysis, we found that the percentage of HLA-DR(+) CD83(+) DCs in metastases was significantly decreased as compared with metastasis-free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF-β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF-β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF-β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a(+) and CD83(+) DCs in tumor stroma correlated with TGF-β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF-β in metastasis development. The increased percentage of CD83(+) DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF-β and by other cytokines.
Wang Y, Deng B, Tang W, et al.TGF-β1 secreted by hepatocellular carcinoma induces the expression of the Foxp3 gene and suppresses antitumor immunity in the tumor microenvironment.
Dig Dis Sci. 2013; 58(6):1644-52 [PubMed
] Related Publications
AIM: The purpose of this study was to explore the mechanisms of TGF-β1 mediated immunosuppression in tumor stroma.
METHODS: The expression of TGF-β1 was investigated in Huh7, Hep 3B, SGC-7901, Eca-109 and Hepa1-6 cell lines using immunofluorescence. Knocked-down TGF-β1 of the Hepa1-6 cell line was established through lentivirus-based RNA interference. The interference efficiency of the TGF-β1 gene was tested by real-time PCR and ELISA; the expression of Foxp3, IFN-γ and CD83 in CD4(+), CD8(+) or dendritic cells was examined via flow cytometry; and the tumorigenic ability of the cancer cells was investigated in the animal experiments.
RESULTS: The diverse digestive cancer cells were found to secrete TGF-β1, mRNA of which was knocked down by 78 % thanks to lentivirus-based interference in Hepa1-6 cells. Flow cytometry showed that CD4(+)CD25(+)Foxp3(+) regulatory T cells significantly increased in hepatocellular carcinoma patients when compared with those in the healthy controls. The supernatant from Hepa1-6 cells and recombinant TGF-β1 significantly induced the expression of Foxp3 gene in vitro, while that from sh TGF-β1 Hepa1-6 cells restored it. Hepa1-6 cells inhibited IFN-γ and CD83 expression in CD8(+) or dendritic cells by secreting TGF-β1. The animal experiments indicated that the knockdown TGF-β1 gene impaired the tumorigenic ability of Hepa1-6 cells.
CONCLUSION: TGF-β1, expressed in cancer cells, might be a potential therapeutic target for cancer treatment.
Xue G, Cheng Y, Ran F, et al.SLC gene-modified dendritic cells mediate T cell-dependent anti-gastric cancer immune responses in vitro.
Oncol Rep. 2013; 29(2):595-604 [PubMed
] Related Publications
Dendritic cells (DCs) are potent professional antigen-presenting cells (APCs) with the ability to prime naïve T cells, and play an important role in the initiation and regulation of immune responses. In this study, we constructed a recombinant adenovirus carrying the SLC gene (Ad-SLC), and detected the biological effects of Ad-SLC-modified DCs as an adjuvant for the initiation of gastric cancer immune responses. Human DCs were transfected with Ad-SLC and the recombinant adenovirus carrying the β-galactosidase gene, Ad-LacZ, respectively. Modified DCs were pulsed with the cell lysate antigen of SGC-7901 cells (a type of gastric cancer cell line) and co-cultured with autologous T cells. The T cells were harvested and incubated with SGC-7901 cells and the cytotoxic function of the T cells was detected. Based on the data, the expression of mature DC phenotypes CD83 and CCR7 was upregulated after transfection with Ad-SLC and the chemotaxis function of DCs was augmented after transfection with Ad-SLC. Moreover, the expression of RANTES in DCs was upregulated by Ad-SLC transfection, while expression levels of IL-12p70 and IL-10 were not significantly altered. When co-cultured with autologous T cells, DCs modified with the SLC gene and pulsed with SGC-7901 cell lysates significantly promoted the proliferation of autologous T cells and induced Th1 differentiation, and displayed a strong cytotoxicity to SGC-7901 cells. In conclusion, Ad-SLC promoted DC maturation, enhancing the ability of DCs for T-cell chemotaxis and T-cell stimulation, and induced specific anti-gastric cancer cellular immunity. Recombinant Ad-SLC-modified DCs may be used as an adjuvant to induce an effective anti-gastric cancer immune response.
Germinal centers (GCs) are sites of B-cell clonal expansion, hypermutation, and selection. GCs are polarized into dark (DZ) and light zones (LZ), a distinction that is of key importance to GC selection. However, the difference between the B cells in each of these zones in humans remains unclear. We show that, as in mice, CXCR4 and CD83 can be used to distinguish human LZ and DZ cells. Using these markers, we show that LZ and DZ cells in mice and humans differ only in the expression of characteristic "activation" and "proliferation" programs, suggesting that these populations represent alternating states of a single-cell type rather than distinct differentiation stages. In addition, LZ/DZ transcriptional profiling shows that, with the exception of "molecular" Burkitt lymphomas, nearly all human B-cell malignancies closely resemble LZ cells, which has important implications for our understanding of the molecular programs of lymphomagenesis.
Tittarelli A, González FE, Pereda C, et al.Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients.
Cancer Immunol Immunother. 2012; 61(11):2067-77 [PubMed
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Toll-like receptor 4 (TLR4) is expressed on dendritic cells (DCs), sensing environmental danger molecules that induce their activation and maturation. Recently, we reported a method for the production of therapeutic DCs against melanoma, called tumor antigen-presenting cells (TAPCells), using a heat-shocked allogeneic melanoma cell lysate (TRIMEL) as an activation factor and antigen provider. Since TRIMEL contains endogenous TLR4 ligands, we evaluated the role of TLR4 in TAPCells differentiation by antibody neutralization and the association of a Tlr4 polymorphism (896A/G) (Asp299Gly), determined by PCR-RFLP, with the in vitro activation capacity and the clinical outcome of TAPCells-vaccinated patients. Antibody blocking of monocyte TLR4 inhibited surface expression, determined by flow cytometry, of the major histocompatibility complex class I, CCR7, CD80, CD83 and CD86 on TAPCells, reduced interleukin (IL)-6 and tumor necrosis factor -α gene expression evaluated by qRT-PCR, and also inhibited the TAPCells-mediated interferon-γ (IFN-γ) secretion of melanoma-specific CD8(+) T cells determined by ELISpot (p < 0.01). Moreover, CD8(+) T-cell activation capacity was significantly reduced in TAPCells bearing the TLR4 Asp299Gly receptor (p < 0.05). Finally, TAPCells-vaccinated stage-IV melanoma patients bearing the Tlr4 896G allele showed a shortened post-therapy median survival rate compared with those carrying the Tlr4 896A allele (p < 0.05; log-rank test). Our results indicate that TLR4 is a key receptor for the tumor lysate-mediated in vitro generation of clinically efficient antigen-presenting cells. Further analysis of patients included in different vaccine protocols is necessary for definitively establishing a role for TLR4 polymorphism in clinical responses.
Liang W, Wang XFIn vitro induction of specific anti-tumoral immunity against laryngeal carcinoma by using human interleukin-12 gene-transfected dendritic cells.
Chin Med J (Engl). 2011; 124(9):1357-61 [PubMed
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BACKGROUND: Objective evaluation of the antitumor effect of interleukin-12 (IL-12) gene-transfected dendritic cell (DC) vaccine on laryngeal carcinoma requires in vivo and in vitro tests. The aim of this study was to investigate the function of IL-12 gene transfected DC at initiating specific immune response to laryngeal carcinoma in vitro.
METHODS: Recombinant adenovirus with IL-12 gene was constructed. DCs were isolated from the peripheral blood of patients with laryngeal carcinoma, pulsed with tumor lysate of laryngeal carcinoma cells (DC⁺Ag), and transfected with IL-12 (DC-IL-12⁺Ag). The cells pheotypes including CD83, CD86 and HLA-DR on surface of DCs were assayed by flow cytometry (FCM). The concentration of IL-12 in culture supernatant of DCs and interferon γ (IFN-γ) in culture supernatant of T cells cocultured with DCs were quantified by ELISA. Methyl thiazolys tetrazolium (MTT) was used to evaluate proliferation of autologous T lymphocytes and activation of cytotoxic T lymphocytes (CTL) stimulated by IL-12-transfected DCs pulsed with tumor lysate against laryngeal carcinoma cells.
RESULTS: The recombinant adenovirus expressing IL-12 gene was constructed successfully. Gene-transfected DC plused with tumor lysate with IL-12 (DC-IL-12⁺Ag) expressed higher level of CD83, CD86 and produced higher level of IL-12 than untransfected DCs (DC⁺Ag) (CD83: (60.2 ± 1.8)% vs. (50.7 ± 1.2)%, P < 0.05; CD86: (88.9 ± 2.1)% vs. (78.2 ± 3.9)%, P < 0.05; IL-12: (262.5 ± 3.0) ng/L vs. (103.8 ± 5.1) ng/L, P < 0.05). The proliferation of autologous T lymphocytes and production of IFN-γ stimulated by DC transfected with IL-12 were more obviously than untransfected DCs. Cytotoxicity of CTL stimulated by IL-12-transfected DC pulsed with tumor lysate against laryngeal carcinoma cells were significantly stronger than stimulated by untransfected DC.
CONCLUSION: It is a promising approach for IL-12-transfected DC pulsed with tumor lysate to increase the antitumoral effect.
Cornforth AN, Fowler AW, Carbonell DJ, et al.Characterization of interferon-γ-treated melanoma tumor cells for use in dendritic cell-based immunotherapy.
Cancer Biother Radiopharm. 2011; 26(3):345-51 [PubMed
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Efficient delivery of tumor-associated antigens to professional antigen-presenting cells is important for inducing a response in patients receiving cancer immunotherapy. Interferon-gamma (IFN-γ) is used by the immune system to combat viral and fungal infections by restricting cell proliferation and, in some cases, inducing apoptosis. Using IFN-γ to activate target tumor cells prior to antigen loading of dendritic cells (DCs) may enhance the beneficial qualities of whole-cell tumor vaccines. The incubation of melanoma cell cultures with IFN-γ resulted in an increase in the expression of major histocompatibility complex molecules and ICAM-1 but generally decreased the expression of melanoma-associated tumor antigens. Additionally, important immune-stimulating molecules (heat-shock proteins, high-mobility group box-1 protein, and calreticulin) were also present but differentially regulated by IFN-γ. Loading of DCs with IFN-γ-treated tumor cells resulted in a small but significant increase in the expression of CD83-positive DCs, indicating the initiation of DC maturation (p=0.019). IFN-γ treatment of melanoma cell lines prior to antigen loading of DCs may aid in antigen processing and presentation.
PURPOSE: In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4(+) T-cell responses against survivin in cancer patients.
EXPERIMENTAL DESIGN: We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4(+) T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4(+) T cells were determined.
RESULTS: We first determined previously unknown DP4-restricted CD4(+) T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4-aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti-survivin CD4(+) T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC.
CONCLUSIONS: DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4(+) and CD8(+) T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy.
Fujimura T, Yamasaki K, Hidaka T, et al.A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18) and IFN-β synergistically induce dendritic cell maturation with augmented IL-12 production and suppress melanoma growth.
J Dermatol Sci. 2011; 62(2):107-15 [PubMed
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BACKGROUND: A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18), mimics the bacterial peptidoglycan moiety and acts as a powerful adjuvant that induces cell-mediated immunity.
OBJECTIVE: To investigate the induction of antitumor immune response for malignant melanoma by IFN-β in combination with MDP-Lys (L18) (IFN-MDP-Lys (L18)).
METHODS: Human monocyte-derived DCs (MoDCs) are stimulated with IFN-MDP-Lys (L18) in vitro. We assess the expression of costimulatory molecules on MoDCs by FACS. Moreover, we investigate the induction of Th1 cytokines by real time PCR and ELISA. Further to confirm the anti tumor immune response of IFN-MDP-Lys (L18) therapy, we examine the growth of B16F10 melanoma in vivo.
RESULTS: The stimulation of human MoDCs with IFN-MDP-Lys (L18) significantly augmented the production of IL-12p70, TNF-α, and IL-6 compared to that with MDP or that with IFN-β alone. IFN-MDP-Lys (L18) increased the expression of IL-12p35, IL-12p40, IL-10, TNF-α, IL-6 and IL-1β mRNA by MoDC using real-time PCR. The expression of CD83 and costimulatory molecules CD40, CD80, and CD86 was also augmented in MoDC treated with IFN-MDP-Lys (L18), which resulted in their augmented allogeneic T cell stimulation. In vivo, the administration of IFN-MDP-Lys (L18) significantly suppressed the growth of B16F10 melanoma, while the monotherapy of IFN-β or MDP-Lys (L18) did not significantly affect the tumor growth.
CONCLUSION: These findings suggest that IFN-MDP-Lys (L18) can be a promising adjuvant therapy for malignant melanoma.
Roy S, Goswami S, Bose A, et al.Neem leaf glycoprotein partially rectifies suppressed dendritic cell functions and associated T cell efficacy in patients with stage IIIB cervical cancer.
Clin Vaccine Immunol. 2011; 18(4):571-9 [PubMed
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Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.
Ismail M, Morgan R, Harrington K, et al.Immunoregulatory effects of freeze injured whole tumour cells on human dendritic cells using an in vitro cryotherapy model.
Cryobiology. 2010; 61(3):268-74 [PubMed
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Tumour cryotherapy has been described as both immunostimulatory and immunoinhibitory in previous studies. However, previous studies have not accurately reproduced the precise conditions of current clinical cryotherapy. The objective of this study is to assess the immunological effects of cryotreated whole tumour cells on dendritic cells (DC) maturation and function using an in vitro model. Prostate cancer cells were cooled using Endocare cryo-system to mimic temperatures achieved during clinical cryotherapy. Human DC were prepared from cluster of differentiation (CD) 14 monocytes and matured with lipopolysaccharide (LPS). Cryotreated cancer cells were added to DC on day 3. On day 7, DC were harvested and phenotyped. Cytokine gene expression was assessed using real time quantitative polymerase chain reaction (RT-PCR). Functional activity of DC was assessed in allogenic mixed lymphocyte reaction (MLR) and the molecular changes using gene microarray technology. There was statistically significant upregulation of costimulatory molecules and maturation markers (CD86, CD83, CD80 and CL II) in DC loaded with cryotreated whole tumour cells compared to both control DC and DC matured with LPS (P < 0.001). There was a significant increase in stimulatory cytokines gene expression (IL-2, IL-12, IL-15, IL-18 and IFN-γ). However, IL-10 and TGF-β expression reduced significantly. The effect of different freezing temperature was equal. cDNA microarray analysis showed upregulation of interleukin 1 (IL-1) and cycline dependent kinase inhibitor 1A (CDKN1A (p21) and downregulation of Caspase 8 and BCL2. Overall, our findings suggest that the effect of cryotherapy is generally stimulatory to DC which may enhance anti-tumour effects. Therefore, the combination of cryotherapy and DC vaccine may represent a novel method to increase the efficacy of cryotherapy especially at the peripheral zones of the prostate where cells are exposed to sub-lethal temperature.
Yu X, Xia W, Zhang T, et al.Enhanced cytotoxicity of IL-24 gene-modified dendritic cells co-cultured with cytokine-induced killer cells to hepatocellular carcinoma cells.
Int J Hematol. 2010; 92(2):276-82 [PubMed
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As a novel human cytokine found recently, IL-24 could selectively kill tumor cells by multiple ways. Dendritic cells (DCs) are the major antigen-presenting cells. Recent studies have revealed that IL-24 can promote the antigen-presenting function of DCs. In this study, we evaluated the antitumor effect and mechanism of co-cultured cytokine-induced killer (CIK) cells and autologous DCs modified with IL-24 gene on hepatocellular carcinoma (HCC) cells. DCs and CIK cells were prepared routinely from human peripheral blood mononuclear cells. Recombinant adenovirus AdVGFP/IL-24 (Ad-IL24) was constructed expressing IL-24. IL-24 gene was transduced into DCs via Ad-IL24, the cells obtained were named DC-IL-24. We demonstrated that the expression rates of CD80, CD83, CD1a, HLA-DR, CD40, CXCR4 on DC-IL-24 were significantly increased compared with those of the control group. DC-IL-24 produced markedly higher levels of IL-24, IL-12 and TNF-alpha as compared with those of DCs. On comparison with non-transfected DCs co-cultured with CIK cells, transfected DCs co-cultured with CIK cells had a significant higher lytic activity against SMMC7721 cells, a HCC cell line.
Bobryshev YV, Lu J, Lord RVExpression of C1q complement component in Barrett's esophagus and esophageal adenocarcinoma.
J Gastrointest Surg. 2010; 14(8):1207-13 [PubMed
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AIMS: C1q, an element of the first component of complement, is known to be expressed by interdigitating and follicular dendritic cells in the spleen, where it has been suggested that C1q is involved in capturing immune complexes. The present study investigated whether C1q is expressed in Barrett's esophagus and esophageal adenocarcinoma and, if so, whether its expression is associated with dendritic cells.
MATERIAL AND METHODS: Endoscopic biopsy or operative surgical specimens were obtained from 15 patients with Barrett's esophagus, 13 patients with esophageal adenocarcinoma and 12 patients whose biopsy specimens did not show the presence of specialized intestinal metaplasia or adenocarcinoma. Barrett's esophagus was diagnosed by the presence of a macroscopic area of columnar-lined esophagus as well as microscopic intestinal metaplasia with goblet cells. Immunohistochemistry utilizing anti-C1q and markers for dendritic cells and macrophages was performed on sections of tissue samples embedded in paraffin. Double immunostaining with C1q/CD83 and C1q/CD68 was used to analyze the possible co-localization of C1q with dendritic cells and macrophages. The expression of C1q by dendritic cells and macrophages was also examined in in vitro studies using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting.
RESULTS: In all specimens studied, C1q expression was detected as being distributed irregularly throughout the lamina propria. A computerized quantitative analysis showed that C1q expression was significantly higher in tissue specimens without specialized intestinal-type metaplasia than in Barrett's esophagus specimens and specimens with adenocarcinoma. Double immunostaining revealed that dendritic cells and macrophages expressed C1q in all analyzed esophageal specimens. The expression of C1q by dendritic cells and macrophages was also demonstrated in in vitro studies using RT-PCR and Western blotting.
CONCLUSION: The findings suggest that reduced levels of the expression of C1q by dendritic cells and macrophages in the esophagus may play a role in the formation of immune responses associated with the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
BACKGROUND: Dendritic cells (DCs) are often produced by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) stimulation of monocytes. To improve the effectiveness of DC adoptive immune cancer therapy, many different agents have been used to mature DCs. We analyzed the kinetics of DC maturation by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) induction in order to characterize the usefulness of mature DCs (mDCs) for immune therapy and to identify biomarkers for assessing the quality of mDCs.
METHODS: Peripheral blood mononuclear cells were collected from 6 healthy subjects by apheresis, monocytes were isolated by elutriation, and immature DCs (iDCs) were produced by 3 days of culture with GM-CSF and IL-4. The iDCs were sampled after 4, 8 and 24 hours in culture with LPS and IFN-gamma and were then assessed by flow cytometry, ELISA, and global gene and microRNA (miRNA) expression analysis.
RESULTS: After 24 hours of LPS and IFN-gamma stimulation, DC surface expression of CD80, CD83, CD86, and HLA Class II antigens were up-regulated. Th1 attractant genes such as CXCL9, CXCL10, CXCL11 and CCL5 were up-regulated during maturation but not Treg attractants such as CCL22 and CXCL12. The expression of classical mDC biomarker genes CD83, CCR7, CCL5, CCL8, SOD2, MT2A, OASL, GBP1 and HES4 were up-regulated throughout maturation while MTIB, MTIE, MTIG, MTIH, GADD45A and LAMP3 were only up-regulated late in maturation. The expression of miR-155 was up-regulated 8-fold in mDCs.
CONCLUSION: DCs, matured with LPS and IFN-gamma, were characterized by increased levels of Th1 attractants as opposed to Treg attractants and may be particularly effective for adoptive immune cancer therapy.
Villablanca EJ, Raccosta L, Zhou D, et al.Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses.
Nat Med. 2010; 16(1):98-105 [PubMed
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Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.