TFAM deficiency in dendritic cells leads to mitochondrial dysfunction and enhanced antitumor immunity through cGAS-STING pathway.

BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors. METHODS: Mouse tumor models were applied to analyze the effect of TFAM deficiency in myeloid cell lineage on tumor progression and tumor microenvironment (TME) modification. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were used in the investigation of the altered function and the activated pathway. OVA was used as the model antigen to validate the activation of immune responses in vivo. STING inhibitors were used to confirm the STING activation provoked by Tfam deficient in DCs. RESULTS: The deletion of TFAM in DCs led to mitochondrial dysfunction and mtDNA cytosolic leakage resulting in the cGAS-STING pathway activation in DCs, which contributed to the enhanced antigen presentation. The deletion of TFAM in DCs has interestingly reversed the immune suppressive TME and inhibited tumor growth and metastasis in tumor models. CONCLUSIONS: We have revealed that TFAM knockout in DCs ameliorated immune-suppressive microenvironment in tumors through STING pathway. Our work suggests that specific TFAM knockout in DCs might be a compelling strategy for designing novel immunotherapy methods in the future.

Genetically modified cancer vaccines: Current status and future prospects.

Vaccines can stimulate the immune system to protect individuals from infectious diseases. Moreover, vaccines have also been applied to the prevention and treatment of cancers. Due to advances in genetic engineering technology, cancer vaccines could be genetically modified to increase antitumor efficacy. Various genes could be inserted into cells to boost the immune response, such as cytokines, T cell costimulatory molecules, tumor-associated antigens, and tumor-specific antigens. Genetically modified cancer vaccines utilize innate and adaptive immune responses to induce durable antineoplastic capacity and prevent the recurrence. This review will discuss the major approaches used to develop genetically modified cancer vaccines and explore recent advances to increase the understanding of engineered cancer vaccines.

Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth.

Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients' prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.

Tubal infertility and pelvic adhesion increase risk of heterotopic pregnancy after in vitro fertilization: A retrospective study.

To analyze risk factors associated with heterotopic pregnancy and the uterine pregnant outcome of those patients after surgery.We retrospectively analyzed 22 patients diagnosed as HP after in vitro fertilization (IVF) between January 2015 and December 2018.HP was diagnosed at gestation age of 55.4 ±â€Š11.8 days. HP were presented as irregular vaginal bleeding, abdominal pain, and sometimes no symptoms. 81.8% of ectopic lesion in HP occurred at fallopian tubes, especially ampullary; cornual pregnancy takes up 13.6%. Compared with clinical intrauterine pregnancy (IUP), IVF with tubal infertility factors had higher risks of HP (OR 4.185, 95% CI 1.080- 16.217); IVF with pelvic adhesion also had higher risks of HP (OR 5.552 95% CI 1.677-18.382); IVF with more than 2 embryos transferred increased risks of HP (OR 23.253, 95% CI 1.804-299.767). The abortion rates of surgery-treated HP and IUP after IVF were 27.8% versus 10.3% (P = .042).These results demonstrate IVF with tubal infertility, pelvic adhesion or multiembryos transfer are risk factors of HP. Furthermore, surgery could induce abortion.

Characteristics and long-term outcomes of perineal endometriosis: A retrospective study.

To summarize the clinical features, diagnosis, and treatments of perineal endometriosis (PEM).We retrospectively studied the clinical data of 35 patients with PEM between April 2012 and December 2018 in West China Second Hospital. Patients were divided into the gonadotropins releasing hormone (GnRH) agonist group and non-GnRH agonist group.The main clinical symptom was vulvar painful swellings related to menstrual cycles. Thirty-three patients' lesions (94.29%) were on the episiotomy scar while 1 case was at the opposite side of the scar. We even found 1 nullipara was diagnosed as PEM. Ten patients (28.57%) were found with anal sphincter involvement. All patients received complete excision of PEM. The recurrence rate of GnRH agonist group was 7.69% (1/13), while the rate of non-GnRH agonist group was 18.75% (3/16).Most PEM was associated with episiotomy history, but PEM could also exist in nullipara. Complete excision of PEM was inevitable. The effect of GnRH agonist on recurrence of PEM needs further studies.

Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden.

OBJECTIVES: Stat3 is persistently activated in ovarian cancer cells, with a crucial role in tumour onset and progression. In this study, we examined the anti-tumour effect of a small-molecule inhibitor napabucasin (BBI608) on epithelial ovarian cancer (EOC) in vitro and in vivo, and investigated the underlying molecular mechanism of this drug in combination with paclitaxel. MATERIALS AND METHODS: A total of 156 ovarian cancer patient samples were analysed to determine the correlation between pStat3 expression in tumour cells and the prognosis of EOC patients. The anti-tumour effect of BBI608 and/or paclitaxel on ovarian cancer in vitro was evaluated by CCK-8, flow cytometry, Western blot and transwell assays. An in vivo intraperitoneal model was performed to confirm the effect of BBI608 on pStat3-mediated peritoneal metastasis when combined with paclitaxel. RESULTS: Patients with high expression of pStat3 had poorer overall survival and progression-free survival than those with low pStat3 expression. The synergy of BBI608 in combination with paclitaxel exerted dramatic growth inhibition and induced apoptosis in EOC cell lines. In vivo, the combination of two drugs significantly decreased intraperitoneal tumour burden and ascites volume, prolonged survival of tumour-bearing mice compared with each monotherapy; these results were associated with downregulation of phospho-Stat3 and activation of apoptosis pathway. CONCLUSIONS: Targeting the activation of Stat3 may be a potential therapeutic approach for EOC by acting synergistically with paclitaxel.

Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer.

Jumonji domain-containing 6 (JMJD6) is a candidate gene associated with tumorigenesis, and JMJD6 overexpression predicts poor differentiation and unfavorable survival in some cancers. However, there are no studies reporting the expression of JMJD6 in ovarian cancer, and no JMJD6 inhibitors have been developed and applied to targeted cancer therapy research. In the present study, we found that the high expression of JMJD6 in ovarian cancer was correlated with poor prognosis in ovarian cancer. A potential inhibitor (SKLB325) was designed based on the crystal structure of the jmjC domain of JMJD6. This molecule significantly suppressed proliferation and induced apoptosis in a dose-dependent manner in SKOV3 cell lines as detected by CCK-8 cell proliferation assays and flow cytometry. A Matrigel endothelial tube formation assay showed that SKLB325 inhibited capillary tube organization and migration in HUVECs in vitro. We also observed that JMJD6 colocalized with p53 protein in the nucleus, with mRNA and protein expression of p53 as well as its downstream effectors significantly increasing both in vitro and in intraperitoneal tumor tissues treated with SKLB325. In addition, SKLB325 significantly reduced the intraperitoneal tumor weight and markedly prolonged the survival of tumor-bearing mice. Taken together, our findings suggest that JMJD6 may be a marker of poor prognosis in ovarian cancer and that SKLB325 may be a potential candidate drug for the treatment of ovarian cancer.

Current strategies against persistent human papillomavirus infection (Review).

Human papillomavirus (HPV) is the most common sexually transmitted infection, exhibiting a tropism for the epidermis and mucosae. The link between persistent HPV infection and malignancies involving the anogenital tract as well as the head and neck has been well­established, and it is estimated that HPV­related cancers involving various anatomical sites account for 4.5% of all human cancers. Current prophylactic vaccines against HPV have enabled the prevention of associated malignancies. However, the sizeable population base of current infection in whom prophylactic vaccines are not applicable, certain high­risk HPV types not included in vaccines, and the vast susceptible population in developing countries who do not have access to the costly prophylactic vaccines, put forward an imperative need for effective therapies targeting persistent infection. In this article, the life cycle of HPV, the mechanisms facilitating HPV evasion of recognition and clearance by the host immune system, and the promising therapeutic strategies currently under investigation, particularly antiviral drugs and therapeutic vaccines, are reviewed.