PLGA Nanoparticles Codelivering siRNAs against Programmed Cell Death Protein-1 and Its Ligand Gene for Suppression of
Seo Young Kwak1, Seonmin Lee, Hee Dong Han2
1Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea.
Abstract:
Tumor-infiltrating T lymphocytes highly express programmed cell death protein-1 (PD-1) that interacts with its ligand, programmed cell death protein ligand-1 (PD-L1) on tumors. PD-1/PD-L1 interactions cause functional exhaustion of effector T cells and impair antitumor immunity, allowing tumors to escape immune surveillance. In addition to such extrinsic interactions, tumors proliferate by transmitting intrinsic PD-L1 signals via the mTOR pathway. Here, we simultaneously silenced PD-1 and PD-L1 expressions on CTLs and colon tumors using PD-1 siRNA/PD-L1 siRNA-loaded PLGA nanoparticles and investigated functional activation of tumor-specific CTLs. When compared to a single PD-1 silencing on CTLs or a single PD-L1 silencing on tumors, cosilencing of PD-1/PD-L1 on CTLs and tumors more efficiently promoted effector functions of tumor-specific CTLs. Moreover, PD-L1-silenced tumors inhibited mTOR signaling and showed an antiproliferative response independent of the adaptive immune response. Ultimately, systemic administration of PD-1 and PD-L1 siRNA via PLGA nanoparticles restored the effector functions of tumor-specific CTLs in MC38 tumor-bearing mice. Compared with antitumor effects of single silencing of PD-1 or PD-L1 alone, cosilencing of PD-1 and PD-L1 showed more significant tumor growth suppression and long-term tumor inhibition in colon cancer. Thus, this study provides an efficient therapeutic strategy for achieving immunotherapy in colon cancer.
Insights
Simultaneously silencing programmed cell death protein-1 (PD-1) and its ligand PD-L1 using nanoparticles enhances T cell responses against colon cancer. This dual silencing strategy shows superior tumor growth suppression and long-term inhibition compared to single-target approaches.
Area of Science:
- Immunology
- Oncology
- Nanotechnology
Background:
- Tumor-infiltrating T lymphocytes express PD-1, interacting with tumor PD-L1, leading to T cell exhaustion and immune evasion.
- Tumors also utilize intrinsic PD-L1 signals via the mTOR pathway for proliferation.
- Current immunotherapies face challenges in overcoming tumor immune suppression.
Purpose of the Study:
- To investigate the efficacy of simultaneously silencing PD-1 on T cells and PD-L1 on colon tumors.
- To evaluate the impact of this dual silencing on tumor-specific CTL functions and antitumor immunity.
- To establish an efficient nanoparticle-based therapeutic strategy for colon cancer immunotherapy.
Main Methods:
- Utilized PD-1 siRNA and PD-L1 siRNA loaded PLGA nanoparticles for simultaneous gene silencing.
- Administered nanoparticles systemically in MC38 colon tumor-bearing mice.
- Assessed effector functions of tumor-specific CTLs and tumor growth inhibition.
Main Results:
- Co-silencing of PD-1 and PD-L1 significantly enhanced effector functions of tumor-specific CTLs compared to single silencing.
- PD-L1 silencing inhibited tumor mTOR signaling, leading to an antiproliferative response independent of adaptive immunity.
- Systemic nanoparticle delivery restored CTL effector functions and demonstrated superior tumor growth suppression and long-term inhibition in mice.
Conclusions:
- Simultaneous silencing of PD-1 and PD-L1 via PLGA nanoparticles is an effective immunotherapy strategy for colon cancer.
- This dual-targeting approach overcomes immune suppression more efficiently than single-target therapies.
- The study provides a promising therapeutic avenue for enhancing antitumor immunity in colon cancer.
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