CCL21/IL21-armed oncolytic adenovirus enhances antitumor activity against TERT-positive tumor cells
VIRUS RESEARCH
Authors: Li, Yang; Li, Yi-fei; Si, Chong-zhan; Zhu, Yu-hui; Jin, Yan; Zhu, Tong-tong; Liu, Ming-yuan; Liu, Guang-yao
Abstract
Multigene-armed oncolytic adenoviruses are capable of efficiently generating a productive antitumor immune response. The chemokine (C-C motif) ligand 21 (CCL21) binds to CCR7 on naive T cells and dendritic cells (DCs) to promote their chemoattraction to the tumor and resultant antitumor activity. Interleukin 21 (IL21) promotes survival of naive T cells while maintaining their CCR7 surface expression, which increases their capacity to transmigrate in response to CCL21 chemoattraction. IL21 is also involved in NK cell differentiation and B cell activation and proliferation. The generation of effective antitumor immune responses is a complex process dependent upon coordinated interactions of various subsets of effector cells. Using the AdEasy system, we aimed to construct an oncolytic adenovirus co-expressing CCL21 and IL21 that could selectively replicate in TERTp-positive tumor cells (Ad-CCL21-IL21 virus). The E1A promoter of these oncolytic adenoviruses was replaced by telomerase reverse transcriptase promoter (TERTp). Ad-CCL21-IL21 was constructed from three plasmids, pGTE-IL21, pShuttle-CMV-CCL21 and AdEasy-1 and was homologously recombined and propagated in the Escherichia coli strain BJ5183 and the packaging cell line HEK-293, respectively. Our results showed that our targeted and armed oncolytic adenoviruses Ad-CCL21-IL21 can induce apoptosis in TERTp-positive tumor cells to give rise to viral propagation, in a dose-dependent manner. Importantly, we confirm that these modified oncolytic adenoviruses do not replicate efficiently in normal cells even under high viral loads. Additionally, we investigate the role of Ad-CCL21-IL21 in inducing antitumor activity and tumor specific cytotoxicity of Cas in vitro. This study suggests that Ad-CCL21-IL21 is a promising targeted tumor-specific oncolytic adenovirus. (C) 2016 Elsevier B.V. All rights reserved.
Shared and Unique Features Distinguishing Follicular T Helper and Regulatory Cells of Peripheral Lymph Node and Peyer's Patches
FRONTIERS IN IMMUNOLOGY
Authors: Georgiev, Hristo; Ravens, Inga; Papadogianni, Georgia; Halle, Stephan; Malissen, Bernard; Loots, Gabriela G.; Forster, Reinhold; Bemhardt, Gunter
Abstract
Follicular helper (TFH) and regulatory (TFR) cells are critical players in managing germinal center (GC) reactions that accomplish effective humoral immune responses. Transcriptome analyses were done comparing gene regulation of TFH and TFR cells isolated from Peyer's Patches (PP) and immunized peripheral lymph nodes (pLNs) revealing many regulatory patterns common to all follicular cells. However, in contrast to TFH cells, the upregulation or downregulation of many genes was attenuated substantially in pLN TFR cells when compared to those of PP. Additionally, PP but not pLN TFR cells were largely unresponsive to IL2 and expressed Il4 as well as Il21. Together with fundamental differences in gene expression that were found between cells of both compartments this emphasizes specific adaptations of follicular T cell functions to their micro-milieu. Moreover, although GL7 expression distinguishes matured follicular T cells, GL7(+) as well as GL7(-) cells are present in the GC.