Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses.
First-generation recombinant adenoviruses that lack E1 sequences have shown tremendous promise in animal and human models of gene therapy. Important limitations of these vectors are that recombinant gene expression is transient and inflammation occurs at the site of gene transfer. Our hypothesis for generating vectors with increased persistence is that present recombinant adenoviruses express viral proteins that stimulate cellular immune responses leading to destruction of the infected cells and repopulation of the organ with non-transgene-containing cells. This model predicts that further crippling of the virus will improve persistence and diminish pathology. We describe in this report second-generation recombinant adenoviruses harboring a beta-galactosidase-expressing transgene in which a temperature-sensitive mutation has been introduced into the E2A gene of an E1-deleted recombinant. At nonpermissive temperature, this virus fails to express late gene products, even when E1 is expressed in trans. The biology of this recombinant was studied in vivo in the context of mouse liver, a setting that is permissive for adenovirus type 5 replication. Animals that received the second-generation virus expressed the transgene for at least 70 days, whereas expression of the first-generation virus was no longer than 14 days. In addition, the inflammatory response, as measured by infiltration of CD8+ T cells, was blunted and delayed in livers infected with second-generation virus. These studies illustrate that modifications that disrupt structural protein expression in recombinant adenoviruses may be useful in enhancing their utility for gene therapy.
Abstract. Qian HN, Liu GZ, Cao SJ, Feng J, Ye X. The experimental study of ovarian carcinoma vaccine modified by human B7-1 and IFN-γ genes. With the advance of immunology, immunogene therapy is becoming a possible therapeutic alternative to advanced cancer. The aim of tumor immunogene therapy is to enhance the immune response to tumors. Evidence suggests that CD80 (B7-1) and Interferon-gamma (IFN-γ) play important roles in antitumor immunity induced by T lymphocyte. To study the antitumor immune effects of ovarian carcinoma vaccine modified with human B7-1 and IFN-γ genes, we constructed the bicistronic retroviral vector pLXSN, encoding human B7-1 and IFN-γ. In vitro , the primary ovarian carcinoma cells were transduced with the retroviral vector and prepared as a vaccine. Then autologous lymphocytes were irritated with the ovarian carcinoma cells for competition inhibitory cytotoxic testing. The tumor-specific cytotoxic activity was greatly enhanced by the double gene–modified vaccine. In vivo , the tumorigenicity of the double gene–modified ovarian cell line 3AO/B7-1·IFN-γ was evaluated in a human immune reconstituted SCID mice (hu-PBL-SCID) model. The double-gene modification markedly decreases tumor genecity. Together, the results suggest that combining B7-1 and IFN-γ could be a useful therapeutic approach in ovarian cancer.
Tolerance to tumor cell-expressed molecules and selection of cells that evade immune surveillance during tumor progression create effective barriers to immunotherapy. We investigated the cytotoxic T-lymphocyte response to simian virus 40 (SV40) tumor (T/t) antigen in two lineages of transgenic mice bearing the same rat insulin promoter-SV40 T/t antigen (RIP Tag) hybrid gene. RIP1-Tag2 mice, which express Tag as embryos, are tolerant to Tag, whereas RIP1-Tag4 mice, which express the transgene in pancreatic islet beta cells several weeks after birth and develop insulinomas, can be immunized to generate active Tag-specific cytotoxic T lymphocytes as determined by in vitro assays. Indeed, RIP1-Tag4 mice immunized with Tag by SV40 infection prior to the time of endogenous transgene expression also mount an effective in vivo cellular immune response to the Tag-expressing pancreatic beta cells, and Tag-induced tumor growth is significantly delayed (up to 1 year). However, after the transgene is expressed, RIP1-Tag4 mice are unable to mount a tumor-inhibiting response upon immunization, although Tag-specific cytotoxic T cells can still be demonstrated in vitro. Our data suggest that Tag-specific T cells are rendered unresponsive in vivo in RIP1-Tag4 mice and that the establishment of this unresponsiveness to Tag can be prevented by SV40 immunization only before the onset of the transgene expression. In the older, successfully immunized mouse, decreased immune surveillance and selection of cells with down-regulation of major histocompatibility complex class I expression most likely set the stage for insulinoma development.
Abstract Activation of Gasdermin D (GSDMD) results in its cleavage, oligomerization, and subsequent formation of plasma membrane pores, leading to a form of inflammatory cell death denoted as pyroptosis. The roles of GSDMD in inflammation and immune responses to infection are well documented. However, whether GSDMD also plays a role in sporadic cancer development, especially that in the gut epithelium, remains unknown. Here, we show that GSDMD is activated in colorectal tumors of both human and mouse origins. Ablation of GSDMD in a mouse model of sporadic colorectal cancer resulted in reduced tumor formation in the colon and rectum, suggesting a tumor-promoting role of the protein in the gut. Both antibiotic-mediated depletion of gut microbiota and pharmacological inhibition of NLRP3 inflammasome reduced the activation of GSDMD. Loss of GSDMD resulted in reduced infiltration of immature myeloid cells, and increased numbers of macrophages in colorectal tumors. Activation of GSDMD is also accompanied by the aggregation of the endosomal sorting complex required for transport (ESCRT) membrane repair proteins on the membrane of colorectal tumor cells, suggesting that active membrane repairment may prevent pyroptosis induced by the formation of GSDMD pore in tumor cells. Our results show that gut microbiota/NLRP3-mediated activation of GSDMD promotes the development of colorectal tumors, and supports the use of NLRP3 inhibitors to treat colon cancer.
As a promising biomarker, human epididymis protein 4 (HE4) has been widely used for the early detection and differential diagnosis of ovarian cancer. This study evaluated the function of HE4 in the carcinogenesis and progression of ovarian cancer. An enzyme immunometric assay, used to detect HE4 in the serum of ovarian cancer patients, showed that the protein could discriminate between malignant and benign ovarian tumours with high specificity. An exogenous HE4 gene was transfected into ovarian cancer cell lines and an immortalized ovarian epithelial cell line. Compared with the controls, HE4 overexpression significantly promoted cell apoptosis and adhesion. Overexpression of HE4 also led to significant inhibition of cell proliferation, migration and invasiveness in vitro, as well as xenograft tumour formation in vivo. This is the first report to demonstrate the functional importance of HE4 in multiple cellular processes and indicates that HE4 may play a protective role in the progression of ovarian cancer.
Objective: To compare the clinical and prognostic characteristics of ovarian endometrioid carcinoma (OEC) patients with synchronous endometrial lesions and patients with pure OEC. Methods: A retrospective review of the medical records of patients received initial treatment and a postoperative pathological diagnosis of OEC at Peking University People's Hospital between August 1998 and December 2017 were performed. According to the inclusion criteria, a total of 56 patients with OEC were included in the study, including 13 patients concurrent with simultaneous endometrial lesions (Group A) and 43 patients with pure OEC (Group B). Results: Patients with synchronous endometrial lesions accounted for 23% (13/56). Mean age of Group A at diagnosis was (44.9±8.3) years old, 2/13 of patients were postmenopausal, and no one had a history of hypertension, the first symptom of 5/13 people was irregular vaginal bleeding. Mean age of Group B patients at diagnosis was (52.7±10.2) years old, 53% (23/43) of patients were postmenopausal, and 28% (12/43) patients had the history of hypertension, the first symptom of 4 (9%, 4/43) people was irregular vaginal bleeding. The differences of age, menopause status, history of hypertension and initial symptoms between the two groups were statistically significant (all P 0.05). The overall 5-year survival rate of OEC patients was 91.6%, and the overall 5-year progression-free survival rate was 76.6%. Among them, the 5-year survival rate of the OEC concurrent with simultaneous endometrial lesions group was 80.2%, and the pure OEC group was 93.4%; the 5-year progression-free survival rate of the OEC concurrent with simultaneous endometrial lesions group was 74.1%, and the 5-year progression-free survival rate of the pure OEC group was 77.3%. There were no significant differences between the two groups (all P>0.05). Multivariate analysis showed that the independent factors for the prognosis of OEC patients were FIGO stage (P=0.006) and residual lesion size (P=0.020). Conclusions: OEC patients have a high proportion of simultaneous endometrial lesions. OEC with simultaneous endometrial lesions are younger than patients with pure OEC. Synchronous endometrial lesions do not affect the prognosis of patients with OEC.
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