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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
M2pep-Modified Cyclodextrin-siRNA Nanoparticles Modulate the Immunosuppressive Tumor Microenvironment for Prostate
Yao Sun1, Michael F Cronin1, Monique C P Mendonça1
1School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland.
Abstract:
Prostate cancer (PCa) is the most prevalent cause of cancer deaths in men. Conventional strategies, such as surgery, radiation, or chemotherapy, face challenges including poor prognosis and resistance. Therefore, the development of new improved strategies is vital to enhance patient outcomes. Recently, immunotherapy has shown potential in the treatment of a range of cancers, including PCa. Tumor-associated macrophages (TAMs) play an important role in the tumor microenvironment (TME) and reprogramming of TAMs is associated with remodeling the TME. The colony-stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) signaling pathway is closely related to the polarization of TAMs. The downregulation of CSF-1R, using small interfering RNA (siRNA), has been shown to achieve the reprogramming of TAMs, from the immunosuppressive M2 phenotype to the immunostimulatory M1 one. To maximize specific cellular delivery an M2 macrophage-targeting peptide, M2pep, was formulated with an amphiphilic cationic β-Cyclodextrin (CD) incorporating CSF-1R siRNA. The resulting nanoparticles (NPs) increased M2 macrophage targeting both in vitro and in vivo, promoting the release of M1 factors and simultaneously downregulating the levels of M2 factors through TAM reprogramming. The subsequent remodeling of the TME resulted in a reduction in tumor growth in a subcutaneous PCa mouse model mainly mediated through the recruitment of cytotoxic T cells. In summary, this M2pep-targeted CD-based delivery system demonstrated significant antitumor efficacy, thus presenting an alternative immunotherapeutic strategy for PCa treatment.
Insights
This study developed targeted nanoparticles to reprogram immunosuppressive M2 macrophages to immunostimulatory M1 macrophages. This novel immunotherapy strategy significantly reduced prostate cancer tumor growth in mice.
Area of Science:
- Immunotherapy
- Nanotechnology
- Oncology
Background:
- Prostate cancer (PCa) remains a leading cause of cancer mortality in men, with conventional treatments facing limitations like resistance and poor prognosis.
- Immunotherapy offers a promising alternative for PCa treatment, with tumor-associated macrophages (TAMs) playing a critical role in the tumor microenvironment (TME).
- The colony-stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) pathway influences TAM polarization, with M2 (immunosuppressive) to M1 (immunostimulatory) reprogramming being a therapeutic goal.
Purpose of the Study:
- To develop a targeted delivery system for reprogramming TAMs in prostate cancer.
- To investigate the efficacy of M2pep-targeted nanoparticles carrying CSF-1R siRNA for PCa immunotherapy.
Main Methods:
- Formulation of amphiphilic cationic β-Cyclodextrin (CD) nanoparticles incorporating CSF-1R siRNA and an M2 macrophage-targeting peptide (M2pep).
- Evaluation of nanoparticle targeting, TAM reprogramming (M2 to M1 phenotype), and TME modulation in vitro and in vivo.
- Assessment of antitumor efficacy in a subcutaneous PCa mouse model.
Main Results:
- The M2pep-targeted CD-based nanoparticles demonstrated enhanced M2 macrophage targeting, leading to successful TAM reprogramming.
- Reprogramming promoted M1 factor release and reduced M2 factors, remodeling the TME and inhibiting tumor growth.
- Significant reduction in tumor growth was observed, primarily mediated by the recruitment of cytotoxic T cells.
Conclusions:
- The M2pep-targeted CD delivery system effectively reprograms TAMs, offering a novel immunotherapeutic strategy for prostate cancer.
- This approach demonstrates significant antitumor efficacy by modulating the tumor microenvironment and enhancing anti-tumor immunity.
