搜索结果: 'immunocult'

Although initial treatment of ovarian cancer is successful,tumors typically relapse and become resistant to treatment. Because of poor infiltration of effector T cells,patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (small extracellular vesicle,sEV) and plays a key role in ovarian cancer chemoresistance,yet little is known about its role in immunosurveillance. Here,we report the immunomodulatory roles of sEV-pGSN in ovarian cancer chemoresistance. In chemosensitive conditions,secretion of sEV-pGSN was low,allowing for optimal CD8+ T-cell function. This resulted in increased T-cell secretion of IFN$\gamma$,which reduced intracellular glutathione (GSH) production and sensitized chemosensitive cells to cis-diaminedichloroplatinum (CDDP)-induced apoptosis. In chemoresistant conditions,increased secretion of sEV-pGSN by ovarian cancer cells induced apoptosis in CD8+ T cells. IFN$\gamma$ secretion was therefore reduced,resulting in high GSH production and resistance to CDDP-induced death in ovarian cancer cells. These findings support our hypothesis that sEV-pGSN attenuates immunosurveillance and regulates GSH biosynthesis,a phenomenon that contributes to chemoresistance in ovarian cancer. SIGNIFICANCE: These findings provide new insight into pGSN-mediated immune cell dysfunction in ovarian cancer chemoresistance and demonstrate how this dysfunction can be exploited to enhance immunotherapy. View Publication

PURPOSE To assess the potential for CUE-101,a novel therapeutic fusion protein,to selectively activate and expand HPV16 E711-20-specific CD8+ T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors,including head and neck squamous cell carcinoma (HNSCC),cervical,and anal cancers. EXPERIMENTAL DESIGN CUE-101 is an Fc fusion protein composed of a human leukocyte antigen (HLA) complex,an HPV16 E7 peptide epitope,reduced affinity human IL2 molecules,and an effector attenuated human IgG1 Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101,whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model. RESULTS CUE-101 demonstrates selective binding,activation,and expansion of HPV16 E711-20-specific CD8+ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+ T cells in HLA-A2 (AAD) transgenic mice,and anticancer efficacy and immunologic memory was demonstrated in TC-1 tumor-bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy. CONCLUSIONS Consistent with its design,CUE-101 demonstrates selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+ T cells,a favorable safety profile,and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing phase I trial (NCT03978689). View Publication