TY - JOUR
T1 - Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion
AU - Liu, Yang
AU - Wang, Lulu
AU - Song, Qianqian
AU - Ali, Muhammad
AU - Crowe, William N
AU - Kucera, Gregory L
AU - Hawkins, Gregory A
AU - Soker, Shay
AU - Thomas, Karl W
AU - Miller, Lance D
AU - Lu, Yong
AU - Bellinger, Christina R
AU - Zhang, Wei
AU - Habib, Amyn A
AU - Petty, W Jeffrey
AU - Zhao, Dawen
N1 - © 2021. The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/2
Y1 - 2022/2
N2 - Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.
AB - Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.
KW - Adaptive Immunity/drug effects
KW - Animals
KW - B7-H1 Antigen/antagonists & inhibitors
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Dendritic Cells/drug effects
KW - Drug Delivery Systems
KW - Humans
KW - Immune Checkpoint Inhibitors/chemistry
KW - Immunity, Innate/drug effects
KW - Immunotherapy
KW - Interferons/genetics
KW - Mice
KW - Nanoparticles/chemistry
KW - Pleural Cavity/drug effects
KW - Pleural Effusion, Malignant/drug therapy
KW - Tumor Microenvironment/drug effects
KW - Xenograft Model Antitumor Assays
U2 - 10.1038/s41565-021-01032-w
DO - 10.1038/s41565-021-01032-w
M3 - Article
C2 - 34916656
VL - 17
SP - 206
EP - 216
JO - Nature Nanotechnology
JF - Nature Nanotechnology
SN - 1748-3387
IS - 2
ER -