Simultaneous Expression of Th1- and Treg-Associated Chemokine Genes and CD4+, CD8+, and Foxp3+ Cells in the Premalignant Lesions of 4NQO-Induced Mouse Tongue Tumorigenesis.
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ABSTRACT:
SUBMITTER: Yamaguchi H
PROVIDER: S-EPMC8069711 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPL) has been demonstrated, there remains a lack of consensus about an optimal approach that balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune-checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancers, including oral cancer, and therefore they may provide an effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the programmed death receptor 1 (PD-1) immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD-1 immune-checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING, which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD-1 inhibitor was found to restore stimulator of interferon response cGAMP interactor 1 (STING) and CD11c expression and increase the infiltration of CD8+ T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti-PD-1 antibodies to prevent malignant progression of OPLs. PREVENTION RELEVANCE: Oral cancer is an aggressive disease, with an overall survival rate of 50%. Preinvasive histologic abnormalities such as tongue dysplasia represent an early stage of oral cancer; however, there are no treatments to prevent oral carcinoma progression. Here, we combined biomaterials loaded with an immunotherapeutic agent preventing oral cancer progression.
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Project description:The 5-year survival rate for patients with oral squamous cell carcinomas (SCC), including tongue SCC, has not significantly improved over the last several decades. Oral potentially malignant disorders (OPMD), including oral dysplasias, are oral epithelial disorders that can develop into oral SCCs. To identify molecular characteristics that might predict conversion of OPMDs to SCCs and guide treatment plans, we performed global transcriptomic analysis of human tongue OPMD (n = 9) and tongue SCC (n = 11) samples with paired normal margin tissue from patients treated at Weill Cornell Medicine. Compared to margin tissue, SCCs showed more transcript changes than OPMDs. OPMDs and SCCs shared some altered transcripts, but these changes were generally greater in SCCs than OPMDs. Both OPMDs and SCCs showed altered signaling pathways related to cell migration, basement membrane disruption, and metastasis. We suggest that OPMDs are on the path toward malignant transformation. Based on patterns of gene expression, both OPMD and tongue SCC samples can be categorized into subclasses (mesenchymal, classical, basal, and atypical) similar to those seen in human head and neck SCC (HNSCC). These subclasses of OPMDs have the potential to be used to stratify patient prognoses and therapeutic options for tongue OPMDs. Lastly, we identified a gene set (ELF5; RPTN; IGSF10; CRMP1; HTR3A) whose transcript changes have the power to classify OPMDs and SCCs and developed a Firth logistic regression model using the changes in these transcripts relative to paired normal tissue to validate pathological diagnosis and potentially predict the likelihood of an OPMD developing into SCC, as data sets become available.
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Project description:We conducted an experimental database analysis to determine the expression of 61 CD4+ Th subset regulators in human and murine tissues, cells, and in T-regulatory cells (Treg) in physiological and pathological conditions. We made the following significant findings: (1) adipose tissues of diabetic patients with insulin resistance upregulated various Th effector subset regulators; (2) in skin biopsy from patients with psoriasis, and in blood cells from patients with lupus, effector Th subset regulators were more upregulated than downregulated; (3) in rosiglitazone induced failing hearts in ApoE-deficient (KO) mice, various Th subset regulators were upregulated rather than downregulated; (4) aortic endothelial cells activated by proatherogenic stimuli secrete several Th subset-promoting cytokines; (5) in Treg from follicular Th (Tfh)-transcription factor (TF) Bcl6 KO mice, various Th subset regulators were upregulated; whereas in Treg from Th2-TF GATA3 KO mice and HDAC6 KO mice, various Th subset regulators were downregulated, suggesting that Bcl6 inhibits, GATA3 and HDAC6 promote, Treg plasticity; and (6) GATA3 KO, and Bcl6 KO Treg upregulated MHC II molecules and T cell co-stimulation receptors, suggesting that GATA3 and BCL6 inhibit Treg from becoming novel APC-Treg. Our data implies that while HDAC6 and Bcl6 are important regulators of Treg plasticity, GATA3 determine the fate of plastic Tregby controlling whether it will convert in to either Th1-Treg or APC-T-reg. Our results have provided novel insights on Treg plasticity into APC-Treg and Th1-Treg, and new therapeutic targets in metabolic diseases, autoimmune diseases, and inflammatory disorders.
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Project description:The 5-year survival rate for patients with oral squamous cell carcinomas (SCC), including tongue SCC, has not significantly improved over the last several decades. Oral potentially malignant disorders (OPMD), including oral dysplasias, are oral epithelial disorders that can develop into oral SCCs. To identify molecular characteristics that might predict conversion of OPMDs to SCCs and guide treatment plans, we performed global transcriptomic analysis of human tongue OPMD (n=9) and tongue SCC (n=11) samples with paired normal margin tissue from patients treated at Weill Cornell Medicine. Compared to margin tissue, SCCs showed more transcript changes than OPMDs. OPMDs and SCCs shared some altered transcripts, but these changes were generally greater in SCCs than OPMDs. Both OPMDs and SCCs showed altered signaling pathways related to cell migration, basement membrane disruption, and metastasis. We suggest that OPMDs were on the path towards malignant transformation. Based in patterns of gene expression, both OPMD samples and SCC samples can be categorized into subclasses (mesenchymal, classical, basal, and atypical) similar to those seen in human head and neck SCC (HNSCC). These subclasses of OPMDs the potential to be used to stratify patient prognosis and therapeutic options for tongue OPMDs. Lastly, we developed Firth logistic regression models to classify OPMDs and SCCs using a signature gene set ELF5, RPTN, IGSF10, HTR3A, and CRMP1, and this predictive model is amenable to testing as data sets become available. We suggest that changes in these five transcripts relative to paired normal tissue could be used to predict of the likelihood of an OPMD developing into a SCC.
2023-10-08 | GSE202048 | GEO
Project description:ObjectivesTo investigate the role of hepatocyte growth factor (HGF)/c-Met signaling in oral malignant transformation.MethodsWe used immunohistochemistry to investigate HGF and c-Met expression in 53 oral squamous cell carcinoma (OSCC) specimens and 21 adjacent nontumor specimens and evaluated the associations between HGF and c-Met expression and clinicopathological parameters. Additionally, HGF-overexpression transgenic (HGF-Tg) and wild-type (Wt) mice were treated with 4-nitroquinoline-1-oxide (4NQO) to induce oral carcinogenesis for 16 weeks. At 16, 20, and 24 weeks, tongue lesions were collected for clinical observation; estimation of HGF, c-Met, and PCNA expression; apoptosis (TUNEL) assays; and RNA sequencing (RNA-seq).ResultsHGF and c-Met were positively expressed in 92.5% and 64% of OSCC samples, respectively. High HGF expression was significantly associated with smaller tumor size (p = 0.006) and inferior TNM stage (p = 0.032). No correlation between HGF and c-Met levels and other clinical parameters or prognosis was noted. In addition, HGF and c-Met expression was elevated in 4NQO-induced lesions of Wt mice. Compared with Wt mice, HGF-Tg mice have lower tumor incidence, number, volume, and lesion grade. In addition, the percentage of PCNA-positive cells in Wt mice was significantly higher than that in HGF-Tg mice at different time points. At 16 weeks, HGF-Tg mice exhibited less apoptotic cells compared with Wt mice (p < 0.000), and these levels gradually increased until the levels were greater than that of Wt mice at 24 weeks (p < 0.000). RNA-seq data revealed that 140 genes were upregulated and 137 genes were downregulated in HGF-Tg mice. KEGG enrichment analysis showed that upregulated differentially expressed genes (DEGs) are highly correlated with oxidative and metabolic signaling and that downregulated DEGs are related to MAPK and PI3K-AKT signaling.ConclusionsHGF and c-Met expression is upregulated in OSCC tissues and is associated with the occurrence and development of OSCC. HGF overexpression in normal oral epithelial tissue can inhibit 4NQO-induced tumorigenesis potentially through inhibiting proliferation and accelerating apoptosis via MAPK and PI3K-AKT signaling.
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Project description:Type 1 diabetes (T1D) occurs through a breakdown of self-tolerance resulting in the autoimmune destruction of the insulin producing β-islets of the pancreas. A numerical and functional waning of CD4+ Foxp3+ regulatory T (Treg) cells, prompted by a pancreatic IL-2 deficiency, accompanies Th1 autoimmunity and T1D progression in non-obese diabetic (NOD) mice. Recently, we identified a dominant subset of intra-islet Treg cells that expresses the ICOS costimulatory receptor and promotes self-tolerance delaying the onset of T1D. ICOS co-stimulation potently enhances IL-2 induced survival and proliferation, and suppressive activity of Treg cells in situ. Here, we propose an ICOS-dependent mechanism of Treg cell homing to the β-islets during pre-diabetes in the NOD model via upregulation of the CXCR3 chemokine receptor. The islet-specific ICOS+ Treg cell subset preferentially expresses CXCR3 in the pancreatic lymph nodes (pLN) in response to Teff cell-mediated pancreatic inflammation, an expression correlating with the onset and magnitude of IFN-γ production by Teff cells in pancreatic sites. We also reveal that intra-pancreatic APC populations and insulin-producing β, but not α nor δ, islet cells secrete the CXCR3 chemokines, CXCL9, 10 and 11, and selectively promote ICOS+ CXCR3+ Treg cell chemotaxis in vitro. Strikingly, islet-derived Treg cells also produce these chemokines suggesting an auto-regulation of homing by this subset. Unlike ICOS- cells, ICOS+ Treg cells adopt a Th1-like Treg phenotype while maintaining their suppressive capacity, characterized by expression of T-bet and CXCR3 and production of IFN-γ in the draining pLNs. Finally, in vivo neutralization of IFN-γ blocked Treg cell CXCR3 upregulation evincing its role in regulating expression of this chemokine receptor by Treg cells. Thus, CXCR3-mediated trafficking of Treg cells could represent a mechanism of homeostatic immunoregulation during diabetogeneesis.
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Project description:BackgroundCarcinogenesis is a dynamic process which traditional biopsying can not keep up with. Saliva as fluid in the vicinity of the tumor can offer better insights to this process. This study aimed to identify the accuracy of salivary DNA integrity index in differentiating between oral premalignant lesions and oral cancer.Material and methodsThis phase II diagnostic test accuracy study included 93 patients divided into three groups: 30 oral cancer patients, 33 patients with oral premalignant lesions divided into 21 oral lichen planus patients and 12 patients with leukoplakia and 30 normal individuals who acted as controls. Oral rinse was collected from all participants and they all underwent conventional visual and tactile examination, and patients with oral lesions had the diagnosis confirmed by histopathological examination of tissue biopsy. DNA integrity index was determined as the ratio between ALU247 and ALU115 measured by qPCR.ResultsThere was no statistically significant difference regarding ALU115, ALU247 and DNA integrity index between the three study groups. The index was significantly higher in the oral cancer group than the oral lichen planus patients, while no significant difference was found between the oral cancer and the leukoplakia cases. The DNA integrity index sensitivity, specificity, positive and negative predictive values were 73%, 45%, 55% and 65% respectively.ConclusionsSalivary DNA integrity index showed poor diagnostic abilities in differentiating between the oral cancer and premalignant lesions.
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Project description:Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and chemoprevention remain the main risk-reducing modalities for those with hereditary cancer syndromes, as well as high-risk non-hereditary breast lesions such as ADH, ALH, or LCIS. Ductal carcinoma in situ (DCIS) is a preinvasive malignant lesion of the breast that closely mirrors IBC and, if left untreated, develops into IBC in up to 50% of lesions. Certain high-risk patients with DCIS may have a 25% risk of developing recurrent DCIS or IBC, even after surgical resection. The development of breast cancer elicits a strong immune response, which brings to prominence the numerous advantages associated with immune-based cancer prevention over drug-based chemoprevention, supported by the success of dendritic cell vaccines targeting HER2-expressing BC. Vaccination against BC to prevent or interrupt the process of BC development remains elusive but is a viable option. Vaccination to intercept preinvasive or premalignant breast conditions may be possible by interrupting the expression pattern of various oncodrivers. Growth factors may also function as potential immune targets to prevent breast cancer progression. Furthermore, neoantigens also serve as effective targets for interception by virtue of strong immunogenicity. It is noteworthy that the immune response also needs to be strong enough to result in target lesion elimination to avoid immunoediting as it may occur in IBC arising from DCIS. Overall, if the issue of vaccine targets can be solved by interrupting premalignant lesions, there is a potential to prevent the development of IBC.
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Project description:Determine whether 4NQO treatment may modulate gene expression in mouse tongue. C57BL/6J mice were given 4NQO (100ug/ml in drink) for 8 weeks; Non-treated control samples were used for comparison.
2016-05-24 | GSE75374 | GEO
Project description:Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality and may develop from oral premalignant lesions (OPL). An improved molecular classification of OPL may help refining prevention strategies. We identified two main OPL gene-expression subtypes, named immunological and classical, in 86 OPL (discovery dataset). A gene expression-based score was then developed to classify OPL samples from three independent datasets, including 17 (GSE30784),13 (GSE10174) and 15 (GSE85195) OPLs, into either one of the two gene-expression subtypes. Using the single sample gene set enrichment analysis, enrichment scores for immune-related pathways were different between the two OPL subtypes. In OPL from the discovery set, loss of heterozygosities (LOH) at 3p14, 17p13, TP53, 9p21 and 8p22 and miRNA gene expression profiles were analyzed. Deconvolution of the immune infiltrate was performed using the Microenvironment Cell Populations-counter tool. A multivariate analysis revealed that decreased miRNA-142-5p expression (P = 0.0484) and lower T-cell, monocytic and myeloid dendritic cells (MDC) immune infiltration (T-cells, P = 0.0196; CD8 T cells, P = 0.0129; MDC, P = 0.0481; and monocytes, P = 0.0212) were associated with oral cancer development in the immunological subtype only. In contrast, LOH at 3p14 (P = 0.0241), 17p13 (P = 0.0348) and TP53 (P = 0.004) were associated with oral cancer development in the classical subtype only. In conclusion, we identified 2 subtypes of OPLs, namely immune and classical, which may benefit from different and specific personalized prevention interventions.
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