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Publication
Journal: Immunity
January/8/2015
Abstract
Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4(+) T cells are important for the formation of functional lung-resident CD8(+) T cells after influenza virus infection. In the absence of CD4(+) T cells, CD8(+) T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8(+) T cells to the lung airways upon heterosubtypic challenge. CD4(+) T cell-derived interferon-γ was necessary for generating lung-resident CD103(+) CD8(+) Trm cells. Furthermore, expression of the transcription factor T-bet was increased in "unhelped" lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4(+) T cell help. Thus, CD4(+) T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103(+) CD8(+) Trm cells in the lung airways following respiratory infection.
Publication
Journal: International Journal of Cancer
April/17/2006
Abstract
The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n=5) and the responders (n=19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68-1.09) and a specificity of 59% (95% CI: 0.47-0.71)(OR=0.09, p=0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p<0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies.
Publication
Journal: Inflammatory Bowel Diseases
January/6/2010
Abstract
BACKGROUND
The interleukin 10 knockout mouse (IL10-KO) is a model of human inflammatory bowel disease (IBD) used to study host microbial interactions and the action of potential therapeutics. Using Affymetrix data analysis, important signaling pathways and transcription factors relevant to gut inflammation and antiinflammatory probiotics were identified.
METHODS
Affymetrix microarray analysis on both wildtype (WT) and IL10-KO mice orally administered with and without the probiotic VSL#3 was performed and the results validated by real-time polymerase chain reaction (PCR), immunocytochemistry, proteomics, and histopathology. Changes in metabolically active bacteria were assessed with denaturing gradient gel electrophoresis (DGGE).
RESULTS
Inflammation in IL10-KO mice was characterized by differential regulation of inflammatory, nuclear receptor, lipid, and xenobiotic signaling pathways. Probiotic intervention resulted in downregulation of CXCL9 (fold change [FC] = -3.98, false discovery rate [FDR] = 0.019), CXCL10 (FC = -4.83, FDR = 0.0008), CCL5 (FC = -3.47, FDR = 0.017), T-cell activation (Itgal [FC = -4.72, FDR = 0.00009], Itgae [FC = -2.54 FDR = 0.0044]) and the autophagy gene IRGM (FC = -1.94, FDR = 0.01), a recently identified susceptibility gene in human IBD. Consistent with a marked reduction in integrins, probiotic treatment decreased the number of CCL5+ CD3+ double-positive T cells and upregulated galectin2, which triggers apoptosis of activated T cells. Importantly, genes associated with lipid and PPAR signaling (PPARalpha [FC = 2.36, FDR = 0.043], PPARGC1alpha [FC = 2.58, FDR = 0.016], Nr1d2 [FC = 3.11, FDR = 0.0067]) were also upregulated. Altered microbial diversity was noted in probiotic-treated mice.
CONCLUSIONS
Bioinformatics analysis revealed important immune response, phagocytic and inflammatory pathways dominated by elevation of T-helper cell 1 type (TH1) transcription factors in IL10-KO mice. Probiotic intervention resulted in a site-specific reduction of these pathways but importantly upregulated PPAR, xenobiotic, and lipid signaling genes, potential antagonists of NF-kappaB inflammatory pathways.
Publication
Journal: Nature Communications
April/18/2017
Abstract
Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3+ cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A+Foxp3+ and ex-Th17 Foxp3+ cells are converted from IL-17A+Foxp3neg cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A+, ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets. Although all Foxp3-expressing subsets are immunosuppressive, glycolysis is a prominent metabolic pathway exerted only by IL-17A+Foxp3+ cells. Transcriptome analysis and flow cytometry of IL-17A+Foxp3+ cells indicate that Folr4, GARP, Itgb8, Pglyrp1, Il1rl1, Itgae, TIGIT and ICOS are Th17-to-Treg cell transdifferentiation-associated markers. Tumour-associated Th17-to-Treg cell conversion identified here provides insights for targeting the dynamism of Th17-Treg cells in cancer immunotherapy.
Publication
Journal: Gastroenterology
June/2/2016
Abstract
OBJECTIVE
Etrolizumab is a humanized monoclonal antibody against the β7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did.
METHODS
We performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score ≤2, with no individual subscore >1, and mucosal healing was defined as endoscopic score ≤1.
RESULTS
Colon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell-associated genes than patients who did not respond (P < .05). Colonic CD4(+) integrin αE(+) cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4(+) αE(-) cells (P < .0001); granzyme A and integrin αE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMA(high) vs 19% GZMA(low) and 44% ITGAE(high) vs 19% ITGAE(low)). Compared with ITGAE(low) and GZMA(low) patients, patients with ITGAE(high) and GZMA(high) had higher baseline numbers of epithelial crypt-associated integrin αE(+) cells (P < .01 for both), but a smaller number of crypt-associated integrin αE(+) cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%-80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline.
CONCLUSIONS
Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. Larger, prospective studies of markers are needed to assess their clinical value.
Publication
Journal: Physiological Genomics
August/11/2008
Abstract
We have utilized serial analysis of gene expression (SAGE) to analyze the response of human coronary artery endothelial cells (HCAECs) to laminar shear stress (LSS). Primary cultures of HCAECs were exposed to 15 dyn/cm(2) LSS for 24 h in a parallel plate flow chamber and compared with identical same passage cells cultured under static conditions. The expression levels of a number of functional categories of genes were reduced by shear stress including those encoding proteins involved in cell proliferation (CDC10, CDC20, CDC23, CCND1, CCNB1), angiogenesis (ANGPTL4, CTGF, CYR61, ENG, EPAS1, EGFR, LGALS3, PGK1, and SPARC), extracellular matrix and cell-matrix adhesion (EFEMP1, LOXL2, P4HB, FBN1, FN1, ITGA5, ITGAE, ITGAV, ILK, LAMR1) and ATP synthesis (ATP5G3, ATP5J2, ATP5L, ATP5D). We also observed an increase in the LSS-responsive expression of genes encoding stress response proteins, including HMOX1, which is significant since HMOX1 may have anti-inflammatory and vasodilatory vascular effects. The autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2 were also elevated by LSS. ADPKD is associated with vascular malfunction, including the impairment of vasoreactive processes. To our knowledge, this is the first SAGE-based analysis of the shear stress-responsive endothelial cell transcriptome. These immortal data provide a resource for further analyses of the molecular mechanisms underlying the biological response to LSS and contribute to the expanding collection of publicly available SAGE data.
Publication
Journal: Stroke
February/19/2009
Abstract
OBJECTIVE
The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.
METHODS
Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).
RESULTS
In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS.
CONCLUSIONS
The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.
Publication
Journal: Journal of Immunology
April/17/2014
Abstract
The interaction of integrin αE(CD103)β7, often expressed on tumor-infiltrating T lymphocytes, with its cognate ligand, the epithelial cell marker E-cadherin on tumor cells, plays a major role in antitumor CTL responses. CD103 is induced on CD8 T cells upon TCR engagement and exposure to TGF-β1, abundant within the tumor microenvironment. However, the transcriptional mechanisms underlying the cooperative role of these two signaling pathways in inducing CD103 expression in CD8 T lymphocytes remain unknown. Using a human CTL system model based on a CD8(+)/CD103(-) T cell clone specific of a lung tumor-associated Ag, we demonstrated that the transcription factors Smad2/3 and NFAT-1 are two critical regulators of this process. We also identified promoter and enhancer elements of the human ITGAE gene, encoding CD103, involved in its induction by these transcriptional regulators. Overall, our results explain how TGF-β1 can participate in CD103 expression on locally TCR-engaged Ag-specific CD8 T cells, thus contributing to antitumor CTL responses and cancer cell destruction.
Publication
Journal: Human Reproduction
September/11/2011
Abstract
BACKGROUND
Crosstalk between human trophectoderm (TE) and endometrial cells during the implantation window is a complex and not well-understood process. The aims of this study were (i) to evaluate the global gene expression profile in TE cells from Day 5 human blastocysts issued from IVF, (ii) to compare these data with the transcriptomic profile of endometrial cells in stimulated cycles for IVF and (iii) to identify potential early dialogues between maternal and embryonic cells during the implantation window.
METHODS
Endometrial biopsies (n = 18) from normal responder patients were performed on the day of embryo transfer (Day 5 after human chorionic gonadotrophin administration). TE biopsies from five blastocysts donated for research purposes were mechanically extracted. DNA microarray analysis was carried out to identify the specific gene expression profiles and the biological pathways activated during the implantation window in endometrial and TE cells.
RESULTS
Several cytokines (such as PDGFA, placenta growth factor, IGF2BP1 and IGF2BP3) were up-regulated in human TE cells, whereas some of the corresponding receptors (PDGFRA and KDR) were over-expressed in the receptive endometrium, suggesting that these molecules are involved in the early dialogue between blastocyst and maternal endometrial cells. In addition, several adhesion molecules and extracellular matrix proteins (MCAM, ITGAE and LAMA1) were also over-expressed in the TE, while others (ALCAM, CEACAM1, PECAM1, ITGB8 and LAMA2) were restricted to the receptive endometrium.
CONCLUSIONS
The present study shows that several growth factors, cytokines, integrins and adhesion molecules are expressed in the TE and endometrium at the time of implantation. These results could contribute to the understanding of the mechanisms involved in the early dialogue between blastocyst and endometrium during implantation. Such results should be confirmed by further studies.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
April/30/2017
Abstract
Vδ2Vγ9 T cells are the dominant γδ T-cell subset in human peripheral blood. Vδ2 T cells recognize pyrophosphate molecules derived from microbes or tumor cells; hence, they play a role in antimicrobial and antitumor immunity. TGF-β, together with IL-15, induces a regulatory phenotype in Vδ2 T cells, characterized by forkhead box protein P3 (FoxP3) expression and suppressive activity on CD4 T-cell activation. We performed a genome-wide transcriptome analysis and found that the same conditions (TGF-β plus IL-15) strongly enhanced the expression of additional genes in Vδ2 T cells, including IKAROS family zinc finger 4 (IKZF4; Eos), integrin subunit alpha E (ITGAE; CD103/αEβ7), and IL9 This up-regulation was associated with potent IL-9 production as revealed by flow cytometry and multiplex analysis of cell culture supernatants. In contrast to CD4 and CD8 αβ T cells, γδ T cells did not require IL-4 for induction of intracellular IL-9 expression. Upon antigen restimulation of Vδ2 T cells expanded in vitro in the presence of TGF-β and IL-15, IL-9 was the most abundant among 16 analyzed cytokines and chemokines. IL-9 is a pleiotropic cytokine involved in various (patho)physiological conditions, including allergy and tumor defense, where it can promote antitumor immunity. Given the conspicuous sensitivity of many different tumors to Vδ2 T-cell-mediated killing, the conditions defined here for strong induction of IL-9 might be relevant for the development of Vδ2 T-cell-based immunotherapy.
Publication
Journal: Immunology Letters
January/31/2010
Abstract
The information conveyed from dendritic cells (DCs) to naïve CD4(+) T cells has crucial influence on their differentiation toward effector T cells. In an effort to identify DC-derived molecules directly contributing to T cell differentiation, we searched for molecules distinctively expressed between two DC subtypes, which were differentiated from peripheral monocytes by cultivation with GM-CSF (for DC1) or IL-3 (for DC2) in the presence of IL-4 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells, respectively. As the first step to address this issue, we subtracted DC1 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2, whose products are known to reside in other than the nucleus. Intriguingly, many of them were molecules involved in Th2-skewed disease pathologies, such as FN1, ITGAE, GPNMB, PLAUR, FPRL2, LILRB4, SERPINE1, ALOX15, TBXAS1, NCF2, CCL3, IL1RN, SPARC, and STAB1, suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations. We also found that expressions of CYP27A1, PPAP2B, RSAD2, and ABCC3 were up-regulated in DC2, implying their significant function in Th2-deviated states. The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC-derived key molecules for T cell differentiation.
Publication
Journal: British Journal of Haematology
April/19/2012
Abstract
Mantle cell lymphoma (MCL) is an aggressive neoplasm with a short survival. Cases with leukaemic MCL and splenomegaly without adenopathies (non-nodal MCL) may have a more indolent course. To gain insights into the biological features underlying this presentation, we investigated the gene expression profile (GEP) and the IGHV mutational status in a cohort of leukaemic MCL cases. Comparison of MCL with other lymphoproliferative disorders (i.e. splenic marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukaemia) revealed a MCL signature enriched for the following gene categories: mitochondrion, oxidoreductase activity, response to stress, to DNA damage and TP53-pathway. Furthermore, GEP analysis revealed that non-nodal MCL cases were characterized by the down-modulation of the following gene categories: cell projection, actin cytoskeleton organization, cell adhesion (ITGAE, CELSR1, PCDH9) and tumour invasion/progression (PGF, ST14, ETS1, OCIAD1, EZR). Many down-modulated genes were related to the TP53-pathway and to DNA damage response. IGHV status proved unmutated in all nodal and mutated in all non-nodal MCL. Non-nodal leukaemic MCLs display a peculiar clinical presentation, with distinctive biological features, such as mutated IGHV and a transcriptional profile lacking tumour invasion properties, that might contribute to the absence of nodal involvement and to the less aggressive clinical course.
Publication
Journal: OncoImmunology
February/19/2017
Abstract
Although high levels of tumor-infiltrating lymphocytes (TILs) generally correlate with good prognosis in high-grade serous ovarian cancer (HGSC) patients, little is known about the phenotype or specificity of these cells. We have recently demonstrated that TIL expressing the intra-epithelial lymphocyte marker CD103 (official name, integrin αE, ITGAE) abundantly infiltrate HGSCs, strongly correlating with increased disease-specific survival.
Publication
Journal: Gynecologic Oncology
January/6/2016
Abstract
OBJECTIVE
To validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma.
METHODS
Ovarian serous carcinomas (n=112) and solid metastases (n=63; total=175) were analyzed for mRNA expression of APC, BAG3, EGFR, S100A10, ITGAE, MAPK3, TAP1, BNIP3, MMP9, FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with >1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases).
RESULTS
BAG3 (p=0.013), TAP1 (p=0.014), BNIP3 (p<0.001) and MMP9 (p=0.036) were overexpressed in primary tumors, whereas S100A10 (p=0.027) and FASLG (p=0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p=0.022), MAPK3 (p=0.002) and BNIP3 (p=0.004) in the former. In primary carcinomas, higher APC (p=0.003) and MAPK3 (p=0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p=0.029) and MAPK3 (p=0.041) levels were related to primary chemoresistance. Higher BAG3 (p=0.026) and APC (p=0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p=0.002) and shorter overall (p=0.005) and progression-free (p<0.001) survival, the latter finding retained in multivariate analysis (p=0.035).
CONCLUSIONS
Our data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer.
Publication
Journal: Cell Reports
April/8/2020
Abstract
T cell factor 1 (Tcf1) promotes the central memory CD8+ T (TCM) cell differentiation and stemness in lymphoid tissues after systemic infections. It remains unclear whether Tcf1 regulates the CD103high tissue-resident memory CD8+ T (TRM) cell formation in non-lymphoid tissues after mucosal infections. We find that Tcf1 is progressively decreased during lung TRM cell formation. Abrogation of transforming growth factor β (TGF-β) signaling is associated with a loss of CD103+ and reciprocal gain of Tcf1+ cells among TRM precursors in vivo. T-cell-specific ablation of Tcf7 enhances CD103 protein expression in TRM cells and precursors and increases TRM cell numbers after primary and secondary infections. Tcf1 directly binds to the Itgae (encoding CD103) locus and partly inhibits TGF-β-induced CD103 expression. Our study suggests that memory T cell tissue residency and homeostatic proliferation are reciprocally regulated by Tcf1. Tcf1 may play either immunosupportive or immunosuppressive roles in CD8+ T cells, depending on systemic or mucosal infections.
Publication
Journal: Biology of Reproduction
November/25/2008
Abstract
Several leukocyte populations have been described within the pregnant mouse uterus, some of which express the integrin beta 7 (ITGB7). Here we demonstrate that the majority of the ITGB7(+) decidual leukocytes belong to the dendritic cell (DC) lineage. By multiparameter flow cytometric analysis we demonstrated the existence of three distinct DC subsets, characterized by differential expression of ITGA4/ITGB7 (formerly alpha4beta7-integrin) and ITGAE/ITGB7 (formerly alphaEbeta7-integrin). Importantly, the predominant DC subsets reside in distinct microdomains of the Day 9 pregnant mouse uterus. ITGAX(+) ITGAM(med) ITGA4/ITGB7(+) ITGAE(-) (formerly CD11c(+) CD11b(med) alpha4beta7(+) alphaE(-)) cells represent the majority of DCs in the vascular zone (VZ), whereas ITGAX(+) ITGAM(-) ITGAE/ITGB7(+) (formerly CD11c(+) CD11b(-) alphaEbeta7(+)) DCs are mainly located in the lower central decidua basalis (cDB) and the underlying myometrium. A population of ITGAX(+) ITGAM(low) DCs lacking ITGB7 are restricted to the cDB. Confocal microscopy studies show direct contact of VZ DCs with uterine natural killer (uNK) cells, suggesting a functional relationship between both cell populations. Collectively, our data identify three phenotypically distinct DC subsets residing in distinct microdomains of the uterus. The differential expression of ITGA4/ITGB7 and ITGAE/ITGB7 suggests distinct functional roles of the different DC subsets during early pregnancy.
Publication
Journal: Clinical Immunology
October/7/2009
Abstract
The integrin alpha(E)beta(7) is believed to play a key role in retention of lymphocytes in mucosal tissues of gut, urogenital tract and lung. Five common single nucleotide polymorphisms spanning ITGAE, the gene encoding the alpha(E) (CD103) unit, were genotyped in 556 sarcoidosis patients and 465 controls. The -1088 A/G polymorphism was associated with sarcoidosis (P=0.004). An increased risk of disease was found for homozygous carriers of the A allele vs. carriers of the G allele (P=0.001, odds ratio=1.63 [1.22-2.17]). Analysis of lymphocytes from bronchoalveolar lavage and in vitro functional tests showed higher percentages of CD103+CD4+ T cells for the sarcoidosis risk genotype. Radiographic staging at disease outcome revealed prevalence of -1088 AA genotype in patients with fibrosis (P=0.01). A higher proportion of CD103+CD4+ T cells and ITGAE -1088 AA genotype might be associated with fibrosis formation in pulmonary sarcoidosis.
Publication
Journal: Journal for ImmunoTherapy of Cancer
April/7/2021
Abstract
Background: CD8+ tissue-resident memory T (TRM) cells, marked by CD103 (ITGAE) expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy.
Methods: Here, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)).
Results: ITGAE was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ TRM cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion.
Conclusions: Our analyses indeed demonstrate that the presence of CD103+ CD8+ TRM cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.
Keywords: CD8-positive T-lymphocytes; biomarkers; gene expression profiling; immunotherapy; lymphocytes; tumor; tumor-infiltrating.
Publication
Journal: Frontiers in Genetics
August/8/2020
Abstract
Human integrin receptors are important for cell-cell and cell-matrix adhesion in normal epithelial cells. Emerging evidences have indicated integrin members are involved in cancer development and progression as well. However, the expression patterns and clinical significance of the whole integrin family in ovarian cancer (OC) have not yet been well understood. In the present study, we utilized the public datasets including GEPIA, GEO, ONCOMINE, cBioPortal, Kaplan-Meier Plotter, TIMER databases, to analyze the expression and prognostic value of integrin members in OC. We found ITGA3/B4/B6/B7/B8 were abnormally overexpressed in OC; ITGA6 was good prognosis predictor in OC; ITGA3/ B4/B8 were poor prognosis predictor specially in advanced OC patients; elevated ITGA3/B4 might promote metastasis and elevated ITGA3/B8 might promote platinum resistance of OC; ITGA3 and ITGB4 might synergistically or independently regulate cell adhesion and proliferation; ITGA4/AL/AM/AX/B2/B7 showed strong correlations with various tumor immune infiltrates (TILs), especially with pro-tumor immunes cell types like monocyte, M2 macrophage and exhaustion T cells infiltration; ITGAL/AM/B2/B7 and residing memory CD8+ T cells marker ITGAE were specially associated with early OC patients outcome. Our results implied that ITGA3/B4 were important prognostic markers of advanced OC, ITGAL/AM/ B2/B7 were immune associated prognosis markers of early OC, together they might render important therapeutic targets for OC.
Keywords: TIL; drug-resistance; integrin; metastasis; ovarian cancer; prognosis.
Publication
Journal: Clinical Sarcoma Research
January/16/2014
Abstract
BACKGROUND
Gastrointestinal stromal tumors are rare soft tissue sarcomas that typically develop from mesenchymal cells with acquired gain-in-function mutations in KIT or PDGFRA oncogenes. These somatic mutations have been well-characterized, but little is known about inherited genetic risk factors. Given evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations in other cancers, we hypothesized that these signature KIT or PDGFRA mutations may be similarly fundamental to understanding gastrointestinal stromal tumor etiology. Therefore, we examined associations between 522 single nucleotide polymorphisms and seven KIT or PDGFRA tumor mutations types. Candidate pathways included dioxin response, toxin metabolism, matrix metalloproteinase production, and immune and inflammatory response.
METHODS
We estimated odds ratios and 95% confidence intervals for associations between each candidate SNP and tumor mutation type in 279 individuals from a clinical trial of adjuvant imatinib mesylate. We used sequence kernel association tests to look for pathway-level associations.
RESULTS
One variant, rs1716 on ITGAE, was significantly associated with KIT exon 11 non-codon 557-8 deletions (odds ratio = 2.86, 95% confidence interval: 1.71-4.78) after adjustment for multiple comparisons. Other noteworthy associations included rs3024498 (IL10) and rs1050783 (F13A1) with PDGFRA mutations, rs2071888 (TAPBP) with wild type tumors and several matrix metalloproteinase SNPs with KIT exon 11 codon 557-558 deletions. Several pathways were strongly associated with somatic mutations in PDGFRA, including defense response (p = 0.005) and negative regulation of immune response (p = 0.01).
CONCLUSIONS
This exploratory analysis offers novel insights into gastrointestinal stromal tumor etiology and provides a starting point for future studies of genetic and environmental risk factors for the disease.
Publication
Journal: Blood advances
December/6/2018
Abstract
Classical CD16- vs intermediate/nonclassical CD16+ monocytes differ in their homing potential and biological functions, but whether they differentiate into dendritic cells (DCs) with distinct contributions to immunity against bacterial/viral pathogens remains poorly investigated. Here, we employed a systems biology approach to identify clinically relevant differences between CD16+ and CD16- monocyte-derived DCs (MDDCs). Although both CD16+ and CD16- MDDCs acquire classical immature/mature DC markers in vitro, genome-wide transcriptional profiling revealed unique molecular signatures for CD16+ MDDCs, including adhesion molecules (ITGAE/CD103), transcription factors (TCF7L2/TCF4), and enzymes (ALDH1A2/RALDH2), whereas CD16- MDDCs exhibit a CDH1/E-cadherin+ phenotype. Of note, lipopolysaccharides (LPS) upregulated distinct transcripts in CD16+ (eg, CCL8, SIGLEC1, MIR4439, SCIN, interleukin [IL]-7R, PLTP, tumor necrosis factor [TNF]) and CD16- MDDCs (eg, MMP10, MMP1, TGM2, IL-1A, TNFRSF11A, lysosomal-associated membrane protein 1, MMP8). Also, unique sets of HIV-modulated genes were identified in the 2 subsets. Further gene set enrichment analysis identified canonical pathways that pointed to "inflammation" as the major feature of CD16+ MDDCs at immature stage and on LPS/HIV exposure. Finally, functional validations and meta-analysis comparing the transcriptome of monocyte and MDDC subsets revealed that CD16+ vs CD16- monocytes preserved their superior ability to produce TNF-α and CCL22, as well as other sets of transcripts (eg, TCF4), during differentiation into DC. These results provide evidence that monocyte subsets are transcriptionally imprinted/programmed with specific differentiation fates, with intermediate/nonclassical CD16+ monocytes being precursors for pro-inflammatory CD103+RALDH2+TCF4+ DCs that may play key roles in mucosal immunity homeostasis/pathogenesis. Thus, alterations in the CD16+ /CD16- monocyte ratios during pathological conditions may dramatically influence the quality of MDDC-mediated immunity.
Publication
Journal: Mutagenesis
August/8/2012
Abstract
Integrins are transmembrane adhesion molecules that mediate cell-cell and cell-extracellular matrix attachment. Integrins regulate cell growth, proliferation, migration and apoptosis and as a consequence, can have a potential role in tumour progression and metastasis. In this study, we investigated 19 non-synonymous variants in the coding region of the human integrin genes representing 3 beta subunits and 13 alpha subunits, for their potential role in melanoma susceptibility and survival. The variants were selected on the basis of probable functional relevance and theoretical predictions. Our data showed that no genetic variant was significantly associated with survival. However, the variants in ITGA10 and ITGA6 genes showed association with decreased risk, and variants in ITGA2, ITGAE and ITGAM were associated with increased risk of melanoma. The haplotype analysis revealed association of CA haplotype of ITGAE and TAC haplotype of ITGAX with the risk modulation. A prediction analysis of functional effect, homology modelling and multiple sequence alignments of integrin sequences from different species supported our data for linkage of variants in the ITGA2 and ITGAE genes with susceptibility. The amino acid changes in each of these integrin proteins could affect intramolecularly and/or the interaction of the heterodimers. Our experimental data indicated a possible role for some of the variant alleles and/or haplotypes of the integrin genes in melanoma susceptibility, which is augmented by the theoretical analysis performed.
Publication
Journal: Cellular and Molecular Immunology
July/2/2020
Abstract
Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8+ T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103+CD8+ T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103+CD8+ T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103+CD8+ T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8+ T cell response to acute viral infection. There is a reduction in resident CD103+CD8+ T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8+ T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103+CD8+ T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103+CD8+ T cell response to promote protective immunity.
Keywords: CD103; Histone acetylation; LCMV infection; SKI; Smad4; TGFβ.
Publication
Journal: Biology of Reproduction
August/19/2007
Abstract
Haspin is a unique protein kinase expressed predominantly in haploid male germ cells. The genomic structure of haspin (Gsg2) has revealed it to be intronless, and the entire transcription unit is in an intron of the integrin alphaE (Itgae) gene. Transcription occurs from a bidirectional promoter that also generates an alternatively spliced integrin alphaE-derived mRNA (Aed). In mice, the testis-specific alternative splicing of Aed is expressed bidirectionally downstream from the Gsg2 transcription initiation site, and a segment consisting of 26 bp transcribes both genomic DNA strands between Gsg2 and the Aed transcription initiation sites. To investigate the mechanisms for this unique gene regulation, we cloned and characterized the Gsg2 promoter region. The 193-bp genomic fragment from the 5' end of the Gsg2 and Aed genes, fused with EGFP and DsRed genes, drove the expression of both proteins in haploid germ cells of transgenic mice. This promoter element contained only a GC-rich sequence, and not the previously reported DNA sequences known to bind various transcription factors--with the exception of E2F1, TCFAP2A1 (AP2), and SP1. Here, we show that the 193-bp DNA sequence is sufficient for the specific, bidirectional, and synchronous expression in germ cells in the testis. We also demonstrate the existence of germ cell nuclear factors specifically bound to the promoter sequence. This activity may be regulated by binding to the promoter sequence with germ cell-specific nuclear complex(es) without regulation via DNA methylation.
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