Dataset Information

Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles.

ABSTRACT: T cell dysfunction-induced tumor immune escape is particularly severe in glioblastoma (GBM), and significantly affects the efficacy of immunotherapy. It is crucial to innovatively reverse the T cell dysfunction for improving GBM immunotherapy. Herein, T cell dysfunction is remarkably reversed and immunotherapy of GBM is boosted by repurposing the U. S. Food and Drug Administration-approved antidepressant paroxetine (PX) with biomimetic nanoparticles (CS-J@CM/6 NPs). The PX is successfully applied to abrogate T cell sequestration in the bone marrow of GBM-bearing mice and increase their infiltration in tumor. The biomimetic NPs are composed of ultrasmall Cu_2- _x Se NPs, JQ1, and tumor cell membrane modified with CD6, and are efficiently delivered into tumor through the specific interactions between CD6 and activated leukocyte cell adhesion molecule. They ameliorate the T cell dysfunction through the double roles of loaded JQ1, which simultaneously decreases the expression of PD-1 and TIM-3 on T cells, and the expression of PD-L1 on tumor cells. The NP also induces the immunogenic cell death of tumor cells to activate immune response. The synergistic roles of PX and biomimetic CS-J@CM/6 NPs notably enhance the survival of GBM-bearing mice. This work provides new insights into tumor immunotherapy by repurposing "old drugs" with advanced NPs.

SUBMITTER: Wang T

PROVIDER: S-EPMC10037995 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles.

Wang Tingting T Zhang Hao H Han Yaobao Y Zheng Qing Q Liu Hanghang H Han Mengxiao M Li Zhen Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230125 9

T cell dysfunction-induced tumor immune escape is particularly severe in glioblastoma (GBM), and significantly affects the efficacy of immunotherapy. It is crucial to innovatively reverse the T cell dysfunction for improving GBM immunotherapy. Herein, T cell dysfunction is remarkably reversed and immunotherapy of GBM is boosted by repurposing the U. S. Food and Drug Administration-approved antidepressant paroxetine (PX) with biomimetic nanoparticles (CS-J@CM/6 NPs). The PX is successfully applie ...[more]

PMID: 36698265

Similar Datasets

Project description:Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-x Se nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Project description:G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in terminating signals initiated by agonist-bound GPCRs. However, chronic stimulation of GPCRs, such as that which occurs during heart failure, leads to the overexpression of GRKs and maladaptive downregulation of GPCRs on the cell surface. We previously reported the discovery of potent and selective families of GRK inhibitors based on either the paroxetine or GSK180736A scaffold. A new inhibitor, CCG258747, which is based on paroxetine, demonstrates increased potency against the GRK2 subfamily and favorable pharmacokinetic parameters in mice. CCG258747 and the closely related compound CCG258208 also showed high selectivity for the GRK2 subfamily in a kinome panel of 104 kinases. We developed a cell-based assay to screen the ability of CCG258747 and 10 other inhibitors with different GRK subfamily selectivities and with either the paroxetine or GSK180736A scaffold to block internalization of the μ-opioid receptor (MOR). CCG258747 showed the best efficacy in blocking MOR internalization among the compounds tested. Furthermore, we show that compounds based on paroxetine had much better cell permeability than those based on GSK180736A, which explains why GSK180736A-based inhibitors, although being potent in vitro, do not always show efficacy in cell-based assays. This study validates the paroxetine scaffold as the most effective for GRK inhibition in living cells, confirming that GRK2 predominantly drives internalization of MOR in the cell lines we tested and underscores the utility of high-resolution cell-based assays for assessment of compound efficacy. SIGNIFICANCE STATEMENT: G protein-coupled receptor kinases (GRKs) are attractive targets for developing therapeutics for heart failure. We have synthesized a new GRK2 subfamily-selective inhibitor, CCG258747, which has nanomolar potency against GRK2 and excellent selectivity over other kinases. A live-cell receptor internalization assay was used to test the ability of GRK2 inhibitors to impart efficacy on a GRK-dependent process in cells. Our data indicate that CCG258747 blocked the internalization of the μ-opioid receptor most efficaciously because it has the ability to cross cell membranes.

Dataset Information

Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles.

Publications

Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets