Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma
Menée in vitro et à l'aide de modèles murins de glioblastome, cette étude met en évidence les effets synergiques antitumoraux des rayonnements ionisants et de nanoparticules lipidiques chargées en dinaciclib et comportant des anticorps ciblant la protéine PD-L1 des cellules myéloïdes associées à la tumeur
Tumor-associated myeloid cells (TAMCs) are a key driver of immunosuppression and therapy resistance in glioblastoma (GBM). The fact that TAMCs compose up to 50% of the brain tumor mass further highlights the urgent need to develop therapeutic strategy for effective targeting of TAMCs in GBM. Here we report a lipid nanoparticle (LNP) platform capable of actively targeting and delivering therapeutics to mouse and human TAMCs by recognizing highly expressed PD-L1 in TAMCs. We show that LNP encapsulated with dinaciclib robustly eliminated TAMCs from glioma and significantly extended survival of mice in glioma models in combination with radiation therapy. This nanomedicine platform holds great potential for improved treatment of GBM and rapid translation into clinical practice.Tumor-associated myeloid cells (TAMCs) are key drivers of immunosuppression in the tumor microenvironment, which profoundly impedes the clinical response to immune-dependent and conventional therapeutic modalities. As a hallmark of glioblastoma (GBM), TAMCs are massively recruited to reach up to 50% of the brain tumor mass. Therefore, they have recently been recognized as an appealing therapeutic target to blunt immunosuppression in GBM with the hope of maximizing the clinical outcome of antitumor therapies. Here we report a nano-immunotherapy approach capable of actively targeting TAMCs in vivo. As we found that programmed death-ligand 1 (PD-L1) is highly expressed on glioma-associated TAMCs, we rationally designed a lipid nanoparticle (LNP) formulation surface-functionalized with an anti–PD-L1 therapeutic antibody (αPD-L1). We demonstrated that this system (αPD-L1-LNP) enabled effective and specific delivery of therapeutic payload to TAMCs. Specifically, encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into PD-L1–targeted LNPs led to a robust depletion of TAMCs and an attenuation of their immunosuppressive functions. Importantly, the delivery efficiency of PD-L1–targeted LNPs was robustly enhanced in the context of radiation therapy (RT) owing to the RT-induced up-regulation of PD-L1 on glioma-infiltrating TAMCs. Accordingly, RT combined with our nano-immunotherapy led to dramatically extended survival of mice in 2 syngeneic glioma models, GL261 and CT2A. The high targeting efficiency of αPD-L1-LNP to human TAMCs from GBM patients further validated the clinical relevance. Thus, this study establishes a therapeutic approach with immense potential to improve the clinical response in the treatment of GBM and warrants a rapid translation into clinical practice.