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1.
J Mammary Gland Biol Neoplasia ; 27(1): 53-65, 2022 03.
Article in English | MEDLINE | ID: mdl-35088220

ABSTRACT

Immunotherapy has been applied to patients with breast cancer. However, only part of patients benefits from the current immunotherapy. Accurate prediction of individual response to immunotherapy can be beneficial for breast cancer management. CD8+ T cells are the main force of anti-tumor immunity. This study aimed to establish a CD8+ T cell-related gene expression signature for prediction of breast cancer prognostic and immunotherapy efficacy. RNA-seq transcriptomic data was the basics of this research. Weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis established the prognostic signature. We identified 290 CD8+ T cell-related genes in the training set and established a risk-score model based on 8-genes panel (SOCS1, IL10, CAMK4, CXCL13, KIR2DS4, TESPA1, CD70 and ICAM4). Subsequently, univariate Cox regression analysis suggested that high risk-score was a risk factor for breast cancer (HR = 3.1, 95%CI 2.0-4.8, P < 0.001). In tumor microenvironment, high-risk tumors present decreased tumor infiltrating CD8+ T cells and increased M2 macrophages. The low-risk patients may benefit more from immune checkpoint blockade immunotherapy than the high-risk patients. Moreover, breast tumors which sensitive to immune checkpoint inhibitor (ICI) showed higher IL10 expression.


Subject(s)
Breast Neoplasms , Transcriptome , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/therapy , CD8-Positive T-Lymphocytes , Female , Gene Expression Regulation, Neoplastic , Humans , Immunotherapy , Interleukin-10/genetics , Prognosis , Tumor Microenvironment/genetics
2.
J Gen Virol ; 94(Pt 7): 1477-1485, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23515028

ABSTRACT

Enterovirus 71 (EV71) is a causative agent of an array of childhood diseases with severe neurological manifestations implicated. EV71 infection is known to induce caspase-dependent apoptosis in cell cultures and animal models. However, whether an alternative apoptotic pathway independent of caspase activation can be triggered by EV71 infection has not been explored. In this study, we showed that calcium (Ca²âº)-activated calpains are capable of mediating caspase-independent pathway activation during EV71-induced apoptosis in HeLa cells. Results from subcellular fractionation analysis and confocal imaging indicated that during EV71 infection, apoptosis-inducing factor (AIF), a primary mediator of the caspase-independent pathway, became truncated and translocated from the mitochondrion to nucleus. This was accompanied by the release of cytochrome c, and sharply decreased mitochondrial membrane potential. AIF knockdown data indicated significant protection against apoptotic cell death, with greater protection provided by the addition of a pan-caspase inhibitor. The Ca²âº-dependent, calpain isoforms 1 and 2, but not cathepsins, were proven crucial for the altered AIF behaviour as studied by the pharmacological inhibitor and the knockdown approaches. We then analysed Ca²âº dynamics in the infected cells and found elevated levels of mitochondrial Ca²âº. Treatment with ruthenium red, a mitochondrial Ca²âº influx inhibitor, significantly blocked calpain activations and AIF cleavage. Our conclusion was that calpain activation via Ca²âº flux plays an essential role in eliciting an AIF-mediated, caspase-independent apoptotic pathway in EV71-infected cells. These findings should be useful for understanding the virus-induced cytopathology and the impact of Ca²âº homeostasis on EV71 infection.


Subject(s)
Apoptosis Inducing Factor/metabolism , Apoptosis/physiology , Calcium/metabolism , Calpain/metabolism , Enterovirus/pathogenicity , Animals , Cell Line , Cell Nucleus/metabolism , Chlorocebus aethiops , Enterovirus Infections/virology , HeLa Cells , Humans , Mitochondria/metabolism , Vero Cells
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