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Blockading a new NSCLC immunosuppressive target by pluripotent autologous tumor vaccines magnifies sequential
Hong Wu1, Hongyan Li2, Yiqiang Liu1
1Integrative Cancer Center & Cancer Clinical Research Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center School of Medicine, University of Electronic Science and Technology of China, No.55, Section 4, South Ren-min Road, Chengdu, 610042, Sichuan, PR China.
Abstract:
The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes (CTLs) allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy. Nanobiotechnology-engineered autologous tumor vaccines (ATVs) that were camouflaged by tumor cell membrane (TCM) were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells, consequently realizing the sequential immunotherapy. PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice. Immediately afterwards, phosphodiesterase-5 (PDE5) and programmed cell death 1 ligand 1 (PD-L1) dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC. Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor (i.e., l-arginine) exerted robust anti-tumor effects through increasing inducible nitric oxide synthase (iNOS) expression, blockading PDE5 pathway and activating systematic immune responses, which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models. The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.
Insights
This study introduces novel nanobiotechnology-engineered vaccines that overcome tumor defenses and enhance anti-PD-1/PD-L1 therapy by targeting PDE5 and PD-L1, leading to significant lung cancer eradication.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Tumor cells evade immune surveillance by utilizing immunosuppressive targets, hindering therapies like anti-PD-1/PD-L1.
- Insufficient cytotoxic T lymphocyte (CTL) activation and infiltration compromise effective anti-tumor immunity.
Purpose of the Study:
- To develop nanobiotechnology-engineered autologous tumor vaccines (ATVs) for sequential immunotherapy.
- To investigate dual-target co-inhibition of phosphodiesterase-5 (PDE5) and programmed cell death 1 ligand 1 (PD-L1) to overcome NSCLC immunosuppression.
Main Methods:
- Designed ATVs camouflaged with tumor cell membrane (TCM) to enhance CTL infiltration.
- Co-encapsulated a PDE5 inhibitor and an NO donor (l-arginine) within ATVs for sequential immunotherapy.
- Evaluated anti-tumor effects in orthotopic and subcutaneous lung cancer models.
Main Results:
- ATVs demonstrated robust anti-tumor effects by increasing inducible nitric oxide synthase (iNOS) expression.
- Co-inhibition of PDE5 and PD-L1 effectively unfroze the tumor immunosuppressive microenvironment.
- Synergistic eradication of local and abscopal lung tumors was achieved.
Conclusions:
- Developed pluripotent ATVs offer a new strategy to mitigate the immunosuppressive tumor microenvironment.
- This approach magnifies the efficacy of anti-PD-1/PD-L1 immunotherapy for lung cancer treatment.
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