Gene therapy offers an alternative and promising avenue to lung cancer treatment. Here, we used dibenzocyclooctyne (DBCO)-branched primers to construct a PTEN gene nanovector (NP-PTEN) through branch-PCR. NP-PTEN showed the nanoscale structure with biocompatible size (84.7 � 11.2 nm) and retained the improved serum stability compared to linear DNA. When transfected into NCI-H1299 cancer cells, NP-PTEN could overexpress PTEN protein to restore PTEN functions through the deactivation of PI3K-AKT-mTOR signaling pathway to inhibit cell proliferation and induce cell apoptosis. The apoptosis rate of NCI-H1299 cancer cells could reach up to 54.5 % � 4.6 % when the transfection concentration of NP-PTEN was 4.0 μg/mL. In mice bearing NCI-H1299 tumor xenograft intratumorally administrated with NP-PTEN, the average tumor volume and tumor weight was separately reduced by 61.7 % and 63.9 %, respectively, compared with the PBS group on the 18 th day of administration. The anticancer efficacy of NP-PTEN in NCI-H1299 tumor xenograft suggests the promising therapeutic potential of branch-PCR assembled PTEN gene nanovectors in lung cancer gene therapy and also provided more opportunities to introduce two or more tumor suppressor genes as an all-in-one gene nanovector for multiple gene-based cancer gene therapy.
Tumor‐associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)‐1β was among the most abundant cytokines within the in vitro tumor‐macrophage coculture system, and enhanced IL‐1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL‐1β mediated immunosuppression during tumor‐TAMs crosstalk. Mechanistically, we demonstrated that IL‐1β significantly boosted programmed death‐ligand 1 (PD‐L1) expression in tumor cells via the activation of the nuclear factor‐κb signaling cascade. Specifically, IL‐1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation‐dependent manner. IL‐1β sustained and intensified immunosuppression by promoting C‐C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL‐1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti‐PD‐L1 antibody in tumor‐bearing mouse models. Together, this study presents an IL‐1β‐centered immunosuppressive loop between TAMs and tumor cells, highlighting IL‐1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.
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