Similar Datasets
Project description:In the K14-HPV16 transgenic mouse model of squamous carcinogenesis, activation of C5a receptor (C5aR1) in early neoplastic tissues fosters protumorigenic properties of C5aR1+ mast cells and macrophages, and in turn, suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5a receptor (C5aR1) with a peptide antagonist improved efficacy to paclitaxel chemotherapy associated with CXCR3-dependent CD8+ T cell activation. To investigate the effects of combination therapy on the T cell repertoire, we performed deep sequencing of the complementarity-determining region (CDR) 3 of the T cell receptor (TCR)b chain in matched tumor lysates and peripheral blood mononuclear cells (PBMCs). Intratumoral TCRβ clonotypes were hyperexpanded and increasingly detected in matched peripherally-expanded T cell populations, thereby implicating antigen-dependent peripheral priming in response to systemic C5aR1 inhibition.
2018-11-28 | GSE112322 | GEO
Project description:In the K14-HPV16 transgenic mouse model of squamous carcinogenesis, activation of C5a receptor (C5aR1) in early neoplastic tissues fosters protumorigenic properties of C5aR1+ mast cells and macrophages, and in turn, suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5a receptor (C5aR1) with a peptide antagonist improved efficacy to paclitaxel chemotherapy associated with CXCR3-dependent CD8+ T cell activation. To investigate the effects of combination therapy on the T cell repertoire, we performed deep sequencing of the complementarity-determining region (CDR) 3 of the T cell receptor (TCR)b chain in matched tumor lysates and peripheral blood mononuclear cells (PBMCs). Intratumoral TCRβ clonotypes were hyperexpanded and increasingly detected in matched peripherally-expanded T cell populations, thereby implicating antigen-dependent peripheral priming in response to systemic C5aR1 inhibition.
2018-11-28 | GSE112321 | GEO
Project description:Extrinsic C5a Activation Regulates Squamous Carcinogenesis and Limits Clonal T Cell Responses to Chemotherapy
| PRJNA445681 | ENA
Project description:Extrinsic C5a Activation Regulates Squamous Carcinogenesis and Limits Clonal T Cell Responses to Chemotherapy (Blood)
| PRJNA445687 | ENA
Project description:Extrinsic C5a Activation Regulates Squamous Carcinogenesis and Limits Clonal T Cell Responses to Chemotherapy (Skin)
| PRJNA445688 | ENA
Project description:Complement is a critical component of humoral immunity implicated in cancer development; however, its biological contributions to tumorigenesis remain poorly understood. Using the K14-HPV16 transgenic mouse model of squamous carcinogenesis, we report that urokinase (uPA)+ macrophages regulate C3-independent release of C5a during premalignant progression, which in turn regulates protumorigenic properties of C5aR1+ mast cells and macrophages, including suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3+ effector memory CD8+ T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy.
| S-EPMC6246036 | biostudies-literature
Project description:Chronically activated leukocytes recruited to premalignant tissues functionally contribute to cancer development; however, mechanisms underlying pro- versus anti-tumor programming of neoplastic tissues by immune cells remain obscure. Using the K14-HPV16 mouse model of squamous carcinogenesis, we report that B cells and humoral immunity foster cancer development by activating Fcgamma receptors (FcgammaRs) on resident and recruited myeloid cells. Stromal accumulation of autoantibodies in premalignant skin, through their interaction with activating FcgammaRs, regulate recruitment, composition, and bioeffector functions of leukocytes in neoplastic tissue, which in turn promote neoplastic progression and subsequent carcinoma development. These findings support a model in which B cells, humoral immunity, and activating FcgammaRs are required for establishing chronic inflammatory programs that promote de novo carcinogenesis.
| S-EPMC3082507 | biostudies-literature
Project description:BackgroundLung cancer is a common kind of human malignancies. Lung squamous cell carcinoma (LUSC) is a key subtype of lung cancer. Cell cycle plays an important role in the development and occurrence of LUSC, however, there is still a lack of cell cycle-related genes in LUSC diagnosis and prediction of prognosis.MethodsWe identified differentially expressed genes (DEGs) with "limma" package in R software, and determined the biomarkers of LUSC in diagnosing by performing receiver operating characteristic (ROC) curve analysis, the biomarker effectiveness in diagnosing LUSC was assessed by performing five-fold cross-validation with logistic regression. Kaplan-Meier plot and the nomogram assessed the relationship between the biomarker and patient survival, and WB and qRT-PCR detected the biomarker expression in cells and tissues. Flow cytometry detects the role of the biomarker in the cell cycle.ResultsIntegration analysis with The Cancer Genome Atlas (TCGA) database obtained a unique gene related to cell cycle in LUSC (Charged multivesicular body protein 4C, CHMP4C), and the protein of CHMP4C was highly expressed in LUSC tissues. ROC analysis indicated that CHMP4C was a biomarker for the diagnosis of LUSC. Bioinformatic analysis indicated that CHMP4C might be associated with cell cycle in LUSC. CHMP4C knockdown resulted in S-phase arrest of cells with LUSC. According to the survival rate analysis, CHMP4C overexpression indicated poor prognosis in patients with LUSC.ConclusionsCHMP4C regulates the proliferation process of tumor cells through the cell cycle. It can be used as a potential diagnostic and prognostic biomarker for LUSC.
| S-EPMC8411186 | biostudies-literature
Project description:Levels of the N-terminally truncated isoform of p63 (?N p63), well documented to play a pivotal role in basal epidermal gene expression and epithelial maintenance, need to be strictly regulated. We demonstrate here that the anaphase-promoting complex/cyclosome (APC/C) complex plays an essential role in the ubiquitin-mediated turnover of ?Np63? through the M-G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to ?Np63, can suppress the APC/C-mediated proteolysis of ?Np63. Supporting the physiological relevance, of these interactions, both Stxbp4 and an APC/C-resistant version of ?Np63? (RL7-?Np63?) inhibit the terminal differentiation process in 3D organotypic cultures. In line with this, both the stable RL7-?Np63? variant and Stxbp4 have oncogenic activity in soft agar and xenograft tumor assays. Notably as well, higher levels of Stxbp4 expression are correlated with the accumulation of ?Np63 in human squamous cell carcinoma (SCC). Our study reveals that Stxbp4 drives the oncogenic potential of ?Np63? and may provide a relevant therapeutic target for SCC.
| S-EPMC6003458 | biostudies-literature
Project description:PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC5842438 | biostudies-literature